TETRAHYDRONAPHTHYRIDINE, BENZOXAZINE, AZA-BENZOXAZINE AND RELATED BICYCLIC COMPOUNDS FOR INHIBITION OF RORgamma ACTIVITY AND THE TREATMENT OF DISEASE

ABSTRACT

The invention provides certain bicylic heterocyclic compounds of the Formula (I) or pharmaceutically acceptable salts thereof, wherein X 1 , X 2 , R 1 , R 2 , R 3 , R4, and Cy are as defined herein. The invention also provides pharmaceutical compositions comprising such compounds of the Formula (I) or pharmaceutically acceptable salts thereof, and methods of using the compounds of the Formula (I) or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the same for treating diseases or conditions mediated by RORgammaT.

FIELD OF THE INVENTION

The present invention relates to certain bicyclic heterocyclic compounds of the Formula (I) (also referred to herein as the “compounds of the Formula (I)” or “compounds of Formula (I)”) which are antagonists of a Thymocyte/T cell specific variant of Retinoic Acid Receptor-related Orphan Receptor (ROR), RORgammaT. The present invention also provides compositions comprising such compounds, and methods of using such compounds for treating conditions or disorders associated with inappropriate RORgammaT activity, in particular in the treatment and prevention of disease states mediated by RORgammaT. Such disease states may include immune and inflammatory disorders such as rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, and asthma.

BACKGROUND OF THE INVENTION

Upon activation by antigen-presenting cells naïve T helper cells undergo clonal expansion and will ultimately differentiate into cytokine secreting effector T cells, such as Th1 and Th2 subtypes. A third and distinct effector subset has been identified, which plays a key role in providing immunity to bacteria and fungi at mucosal surfaces (Kastelein et al., Annu. Rev. Immunol. 25: 221-242, 2007). This effector T helper cell subset can be distinguished based on its ability to produce large quantities of IL-17/F, IL-21 and IL-22, and is named Th17 (Miossec et al., New Eng. J. Med. 361: 888-898, 2009).

Different T helper subsets are characterized by the expression of lineage specific master transcription factors. Th1 and Th2 effector cells express Tbet and GATA3, respectively. A Thymocyte/T cell specific variant of Retinoic Acid Receptor-related Orphan Receptor (ROR), RORgammaT, is highly expressed in Th17 cells (He et al., Immunity 9: 797-806, 1998). RORgammaT belongs to the nuclear hormone receptor superfamily (Hirose et al., Biochem. Biophys. Res. Comm. 205: 1976-1983, 1994). RORgammaT is a truncated form of RORgamma, lacking the first N-terminal 21 amino acids and is, in contrast to RORgamma which is expressed in multiple tissues (heart, brain, kidney, lung, liver, and muscle), exclusively expressed in cells of the lymphoid lineage and embryonic lymphoid tissue inducers (Sun et al., Science 288: 2369-2372, 2000; Eberl et al., Nat Immunol. 5: 64-73, 2004).

Studies using heterozygous knock-in mice replacing the RORgammaT open reading frame with GFP (green fluorescent protein) revealed a constitutive expression of GFP in approximately 10% of the CD4+ T cells in the small intestinal lamina propria (LP), co-expressing the Th17 cytokines IL-17/F and IL-22 (Ivanov et al., Cell 126: 1121-1133, 2006). In mice deficient for RORgammaT, the number of Th17 cells was markedly decreased in the LP; and in vitro stimulation of CD4+ T cells under Th17 polarizing conditions resulted in a drastic decrease of IL-17 expression. These results were further substantiated via forced expression of RORgammaT in naïve CD4+ T cells, which resulted in an induction of IL-17/F and IL-22 (Ivanov et al., Cell 126: 1121-1133, 2006). The foregoing studies demonstrate the importance of RORgammaT in differentiation and stabilization of the Th17 lineage. In addition, a ROR family member, RORalpha, has been demonstrated to be involved in Th17 differentiation and stabilization (Yang et al., Immunity 28: 29-39, 2008).

Recently, RORgammaT was shown to play a crucial role in non-Th17 lymphoid cells. In these studies, RORgammaT was critically important in innate lymphoid cells expressing Thy1, SCA-1, and IL-23R proteins. Genetic disruption of RORgamma in a mouse colitis model dependent on these innate lymphoid cells prevented colitis development (Buonocore et al., Nature 464: 1371-1375, 2010). In addition, RORgammaT was shown to play a crucial role in other non-Th17 cells, such as mast cells (Hueber et al., J. Immunol. 184: 3336-3340, 2010). Finally, RORgammaT expression and secretion of Th17-type of cytokines was reported for Lymphoid Tissue Inducer cells, NK T-cells, NK cells (Eberl et al., Nat. Immunol. 5: 64-73, 2004) and gamma-delta T-cells (Sutton et al., Immunity 31: 331-341, 2009; Louten et al., J. Allergy Clin. Immunol. 123: 1004-1011, 2009), suggesting an important function for RORgammaT in these subtypes of cells.

Based on the role of IL-17 producing cells (either Th17 or non-Th17 cells) RORgammaT has been identified as a key mediator in the pathogenesis of several diseases (Louten et al., J. Allergy Clin. Immunol. 123: 1004-1011, 2009; Annunziato et al., Nat. Rev. Rheumatol. 5: 325-331, 2009). This was confirmed using several disease models representative of autoimmune diseases. Genetic ablation of the RORgamma gene in mice prevented the development of experimental autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE) and colitis (Ivanov et al., Cell 126:1121-33, 2006; Buonocore et al., Nature 464: 1371-1375, 2010).

With RORgammaT being a critical mediator in Th17-cells and non-Th17 cells, antagonism of the transcriptional activity of RORgammaT is expected to have a beneficial effect on autoimmune diseases, such as but not limited to rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), and asthma (Annunziato et al., Nat. Rev. Rheumatol. 5: 325-331, 2009; Louten et al., J. Allergy Clin. Immunol. 123: 1004-1011, 2009). Antagonism of RORgammaT may also be beneficial in other diseases that are characterized by increased levels of Th17 cells and/or elevated levels of Th17 hallmark cytokines such as IL-17, IL-22 and IL-23. Examples of such diseases are Kawasaki Disease (Jia et al., Clin. Exp. Immunol. 162: 131-137, 2010) and Hashimoto's thyroiditis (Figueroa-Vega et al., J. Clin. Endocrinol. Metab. 95: 953-62, 2010). Another example includes infectious diseases, such as but not limited to mucosal leishmaniasis (Boaventura et al., Eur. J. Immunol. 40: 2830-2836, 2010). In each of the above examples the inhibition may be enhanced by simultaneous inhibition of RORalpha.

Compounds modulating RORgammaT have been reported. Examples of agonists include T0901317 and SR1078 (Wang et al., ACS Chem. Biol. 5:1029-1034, 2010). In addition, antagonists have been reported such as 7-oxygenated sterols (Wang et al., J. Biol. Chem. 285: 5013-5025, 2010) and the compounds described in EP 2181710 A1.

Numerous immune and inflammatory disorders continue to afflict millions of patients worldwide. Although significant advances have been made in treating these disorders, current therapies do not provide satisfactory results for all patients due to, for example, detrimental side effects or insufficient efficacy. One exemplary immune disorder in need of better therapy is psoriasis. Various therapeutics have been developed in an attempt to treat psoriasis. However, the traditional therapies for psoriasis often have toxic adverse effects. An exemplary inflammatory disorder in need of better treatment is rheumatoid arthritis. Numerous therapeutics have been developed in an attempt to treat this disorder. However, some patients develop resistance to current therapies.

Accordingly, a need exists for improved treatments for immune disorders and inflammatory disorders. The present invention addresses this need and provides other related advantages.

SUMMARY OF THE INVENTION

The present invention provides compounds that alter the interaction of coregulator proteins with RORgammaT and thereby antagonize RORgammaT-mediated transcriptional activity; pharmaceutical compositions comprising such compounds and pharmaceutically acceptable excipients; and use of such compounds or such pharmaceutical compositions for the treatment of RORgammaT-mediated diseases or conditions, in particular autoimmune diseases and inflammatory diseases.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof. That notwithstanding and except where stated otherwise, the following definitions apply throughout the specification and claims. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure predominates. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of “alkyl” applies to “alkyl” as well as the “alkyl” portions of “hydroxyalkyl,” “fluoroalkyl,” “—O-alkyl,” etc.

As used herein, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

A “patient” is a human or non-human mammal. In one embodiment, a patient is a human. In another embodiment, a patient is a chimpanzee.

The term “therapeutically effective amount” as used herein refers to an amount of the compound of Formula (I) and/or an additional therapeutic agent, or a composition thereof that is effective in producing the desired therapeutic, ameliorative, inhibitory, or preventative effect when administered to a patient suffering from a disease or condition mediated by RORgammaT. In the combination therapies of the present invention, a therapeutically effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount.

The term “preventing,” as used herein with respect to an inflammatory disease or disorder, refers to reducing the likelihood of an autoimmune or inflammatory disease or disorder.

The term “alkyl,” as used herein, refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond having the specified number of carbon atoms. In different embodiments, an alkyl group contains from 1 to 6 carbon atoms (C₁-C₆ alkyl) or from 1 to 3 carbon atoms (C₁-C₃ alkyl). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl, and neohexyl. In one embodiment, an alkyl group is linear. In another embodiment, an alkyl group is branched.

The term “fluoroalkyl,” as used herein, refers to an alkyl group as defined above, wherein one or more of the alkyl group's hydrogen atoms have been replaced with a fluorine. In one embodiment, a fluoroalkyl group has from 1 to 6 carbon atoms. In another embodiment, a fluoroalkyl group has from 1 to 3 carbon atoms. In another embodiment, a fluoroalkyl group is substituted with from 1 to 3 fluorine atoms. Non-limiting examples of fluoroalkyl groups include —CH₂F, —CHF₂, and —CF₃. The term “C₁-C₃ fluoroalkyl” refers to a fluoroalkyl group having from 1 to 3 carbon atoms.

The term “alkylene,” as used herein, refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a bond. Non-limiting examples of alkylene groups include —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH(CH₃)CH₂CH₂—, —CH(CH₃)—, and —CH₂CH(CH₃)CH₂—. In one embodiment, an alkylene group has from 1 to about 6 carbon atoms (C₁-C₆ alkylene). In another embodiment, an alkylene group has from 1 to 3 carbon atoms (C₁-C₃ alkylene). In another embodiment, an alkylene group is branched. In another embodiment, an alkylene group is linear. In one embodiment, an alkylene group is —CH₂—. The term “C₁-C₃ alkylene” refers to an alkylene group having from 1 to 3 carbon atoms. Unless otherwise indicated, an alkylene group is unsubstituted.

The term “alkenyl,” as used herein, refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and having one of its hydrogen atoms replaced with a bond. An alkenyl group may be straight or branched and contain from about 2 to about 15 carbon atoms. In one embodiment, an alkenyl group contains from about 2 to 4 carbon atoms. Non-limiting examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl, and decenyl. The term “C₂-C₆ alkenyl” refers to an alkenyl group having from 2 to 6 carbon atoms. The term “C₂-C₄ alkenyl” refers to an alkenyl group having from 2 to 4 carbon atoms. Unless otherwise indicated, an alkenyl group is unsubstituted.

The term “alkoxy,” as used herein, refers to an —O-alkyl group, wherein an alkyl group is as defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and tert-butoxy. An alkoxy group is bonded via its oxygen atom to the rest of the molecule.

The term “aryl,” as used herein, refers to an aromatic monocyclic or multicyclic ring system comprising from about 6 to about 14 carbon atoms. In one embodiment, an aryl group contains from about 6 to 10 carbon atoms (C₆-C₁₀ aryl). In another embodiment an aryl group is phenyl. Non-limiting examples of aryl groups include phenyl and naphthyl.

The term “carbocycle,” as used herein, refers to a fully saturated, partially unsaturated, or an aromatic monocyclic or multicyclic ring system comprising from about 6 to 14 carbon atoms. In one embodiment, an aryl group contains from 3 to 10 carbon atoms (C₃-C₁₀ carbocycle). Non-limiting examples of carbocyclic groups include cycloalkyl and aryl groups, as defined herein. In specific embodiments, the carbocyclic groups are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, indanyl, naphthyl, and tetrahydronaphthyl.

The term “cycloalkyl,” as used herein, refers to a saturated ring containing the specified number of ring carbon atoms, and no heteroatom. In a like manner the term “C₃-C₆ cycloalkyl” refers to a saturated ring having from 3 to 6 ring carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term “halo,” as used herein, means —F, —Cl, —Br or —I. In one embodiment, a halo group is —F or —Cl. In another embodiment, a halo group is —F.

“Heterocyclyl” refers to a 4-, 5-, 6-, or 7-membered monocyclic ring or 8-, 9-, or 10-membered bicyclic ring, or 13- or 14-membered tricyclic ring, saturated, unsaturated or aromatic, containing 1, 2, 3, or 4 heteroatoms selected from O, N, or S, and the heterocyclyl may optionally be substituted with one to four substituents. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide, or S,S-dioxide. A heterocyclyl group can be joined to the rest of the molecule via a ring carbon or ring nitrogen atom. Representative heterocyclyls are as follows: azetidinyl, pyrrolidinyl, pyrrolyl, tetrahydrofuran, imidazolyl, imidazolinyl, 1,3-oxazolidinyl, 1,2-oxazolidinyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, pyrimidinyl, pyrrolopyrazine, pyrrolopyridine, and indolyl.

The term “substituted” means that one or more hydrogens on the designated atom/atoms is/are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By “stable compound” or “stable structure” is meant a compound that is sufficiently robust to survive isolation from a reaction mixture to a useful degree of purity, and formulation into an efficacious therapeutic agent.

When any substituent or variable occurs more than one time in any constituent or in the compound of Formula (I), its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated.

When an integer defining the presence of a certain number of atoms in a group is equal to zero, it means that the atoms adjacent thereto are connected directly by a bond; for example, in the structure

wherein s is an integer equal to zero, 1 or 2, the structure is

when s is zero; or it means that the indicated atom is absent; for example, —S(O)₀— means —S—.

The term “in purified form,” as used herein, refers to the physical state of a compound after the compound has been isolated through a synthetic process (e.g., from a reaction mixture), from a natural source, or a combination thereof. The term “in purified form” also refers to the physical state of a compound after the compound has been obtained from a purification process or processes described herein or well-known to the skilled artisan (e.g., chromatography, recrystallization, and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well-known to the skilled artisan.

It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples, and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.

One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves various degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H₂O.

The compounds of Formula (I) may contain one or more stereogenic centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. Any formulas, structures, or names of compounds described in this specification that do not specify a particular stereochemistry are meant to encompass any and all existing isomers as described above and mixtures thereof in any proportion. When stereochemistry is specified, the invention is meant to encompass that particular isomer in pure form or as part of a mixture with other isomers in any proportion.

Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column.

It is also possible that the compounds of Formula (I) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention.

All stereoisomers (for example, geometric isomers, optical isomers, and the like) of the present compounds (including stereoisomers of salts and solvates of the present compounds as well as stereoisomers of salts, solvates, and esters of prodrugs of the present compounds), such as those that may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.

The compounds of Formula (I) can form salts which are also within the scope of this invention. Reference to a compound of Formula (I) herein is understood to include reference to salts thereof, unless otherwise indicated. The term “salt(s),” as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula (I) contains both a basic moiety, such as but not limited to a pyridine or imidazole, and an acidic moiety, such as but not limited to a carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein. Such acidic and basic salts used within the scope of the invention are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts. Salts of the compounds of Formula (I) may be formed, for example, by reacting a compound of Formula (I) with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates), and the like. Additionally, acids that are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference.

Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.

The present invention further includes the compounds of Formula (I) in all their isolated forms. For example, the above-identified compounds are intended to encompass all forms of the compounds, such as any solvates, hydrates, stereoisomers, and tautomers thereof.

As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

In the compounds of generic Formula (I), the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of generic Formula (I). For example, different isotopic forms of hydrogen (H) include protium (¹H) and deuterium (²H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. In light of the present disclosure, isotopically-enriched compounds within generic Formula (I) can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the examples herein using appropriate isotopically-enriched reagents and/or intermediates.

Compounds of the Invention

The present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein X¹, X², R¹, R², R³, R⁴, and Cy are as defined below. Described below are embodiments of the compound of Formula (I). The compound of the Formula (IA), shown below, is an embodiment of the compound of Formula (I).

In embodiment no. 1, the invention provides a compound of Formula (I),

or a pharmaceutically acceptable salt thereof, wherein: X¹ is C(R²) or N; X² is O, S, S(O), S(O)₂, CH₂, or C(O); R¹ is H, C₁-C₃ alkyl, or C₁-C₃ alkyl substituted by hydroxy; R² is H, halo, or C₁-C₃ alkyl; R³ is selected from the group consisting of:

(a.) H;

(b.) C₁-C₆ alkyl;

(c.) —(C(R^(a))₂)_(n1)OH;

(d.) —(C(R^(a))₂)_(n1)N(R^(b))₂;

(e.) —(C(R^(a))₂)_(n1)N(H)C(O)N(R^(b))₂;

(f.) —(C(R^(a))₂)_(n1)N(H)C(O)R^(d);

(g.) —(C(R^(a))₂)_(n1)N(H)S(O)₂N(R^(b))₂;

(h.) —(C(R^(a))₂)_(n1)N(H)S(O)₂R^(d);

(i.) —(C(R^(a))₂)_(n1)CO₂R^(c);

(j.) —(C(R^(a))₂)_(n2)C(O)N(R^(b))₂;

(k.) —(C(R^(a))₂)_(n1)S(O)₂N(R^(b))₂;

(l.) —(C(R^(a))₂)_(n2)N(H)C(O)OR^(d);

(m.) —(C(R^(a))₂)_(n2)C(O)N(H)S(O)₂R^(d);

(n.) —(C(R^(a))₂)_(n1)N(H)S(O)₂OR^(d);

(o.) —(C(R^(a))₂)_(n1)S(O)_(n3)R^(d);

(p.) —(C(R^(a))₂)_(n2)C(O)N(H)OR^(d);

(q.) —(C(R^(a))₂)_(n1)CN;

(r.) —C^(H) or —(C(R^(a))₂)_(n1)—C^(H);

(s.) —C(R^(a))₂O—C^(C);

(t.) —C(O)CF₃;

(u.) —OH, with the proviso that R³ is —OH only when X² is CH₂; and

(v.) —N(R^(b))₂, with the proviso that R³ is —N(R^(b))₂ only when X² is CH₂;

-   -   each R^(a) is independently H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl,         or C₃-C₆ cycloalkyl, or alternatively two R^(a) when bonded to a         common carbon atom may together with the common carbon atom form         a cyclopropyl ring;     -   each R^(b) is independently:         -   (i.) H;         -   (ii.) C₁-C₆ alkyl, wherein said C₁-C₆ alkyl is unsubstituted             or independently substituted by 1 to 3 fluoro, or hydroxyl;         -   (iii.) —(CH₂)_(n3)CO₂R^(e); or         -   (iv.) —C^(C) or —CH₂—C^(C); or         -   alternatively, two R^(b) together with the N atom to which             they are attached form a 5- to 9-membered heterocyclyl,             wherein said heterocyclyl is a saturated, partially             saturated, or aromatic ring system containing 0, 1, or 2             additional heteroatoms independently selected from the group             consisting of N, O, S, and S(O)₂; wherein said heterocyclyl             is unsubstituted or substituted by 1 to 4 moieties             independently selected from the group consisting of C₁-C₆             alkyl, C₁-C₃ alkoxy, fluoro, hydroxyl, oxo, cyano, amino,             C₁-C₃ alkylamino, and C₁-C₃ dialkylamino;     -   R^(c) is         -   (i.) H;         -   (ii.) C₁-C₆ alkyl, wherein said C₁-C₆ alkyl is unsubstituted             or independently substituted by 1 to 3 fluoro or hydroxy; or         -   (iii.) —C^(C) or CH₂—C^(C);     -   R^(d) is         -   (i.) C₁-C₆ alkyl, wherein said C₁-C₆ alkyl is unsubstituted             or independently substituted by 1 to 3 fluoro or hydroxy;         -   (ii). —C(O)N(R^(f))₂; or         -   (iii.) —C^(C) or CH₂—C^(C);     -   R^(e) is H or C₁-C₃ alkyl;     -   R^(f) is H or C₁-C₃ alkyl;     -   ring C^(H) is         -   (i.) C₃-C₆ cycloalkyl;         -   (ii.) phenyl; or         -   (iii.) a 4- to 9-membered mono- or bicyclic heterocyclyl,             wherein said heterocyclyl is a saturated, partially             saturated, or aromatic ring system containing 1 to 4             heteroatoms independently selected from the group consisting             of N, O, S, and S(O)₂;         -   wherein ring C^(H) is unsubstituted or independently             substituted by 1 to 4 C₁-C₆ alkyl, C₁-C₃ alkoxy, halo,             hydroxyl, oxo, cyano, amino, C₁-C₃ alkylamino, or C₁-C₃             dialkylamino;     -   ring C^(C) is         -   (i.) C₃-C₆ cycloalkyl;         -   (ii.) phenyl; or         -   (iii.) a heterocyclyl of the formula

-   -   -    wherein said heterocyclyl is a 5- to 9-membered             heterocyclyl, wherein said heterocyclyl is a saturated,             partially saturated, or aromatic ring system that contains             1, 2, or 3 heteroatoms independently selected from the group             consisting of N, O, S, and S(O)₂;         -   wherein ring C^(C) is unsubstituted or independently             substituted by 1 to 4 C₁-C₆ alkyl, C₁-C₃ alkoxy, halo,             hydroxyl, oxo, cyano, amino, C₁-C₃ alkylamino, or C₁-C₃             dialkylamino;

the subscript n1 is 1, 2, or 3;

the subscript n2 is 0, 1, 2, or 3;

the subscript n3 is 1 or 2;

R⁴ is

-   -   (a.) C₁-C₈ alkyl, wherein said C₁-C₈ alkyl of R⁴ is         unsubstituted or independently substituted by 1 to 6 halo, C₁-C₃         alkoxy, hydroxy, cyano, trimethylsilyl, or methylsulfonyl;     -   (b.) C₂-C₈ alkenyl, wherein said C₂-C₈ alkenyl of R⁴ is         unsubstituted or independently substituted by 1 to 6 fluoro or         cyano; or     -   (c.) a group of the formula -M-R^(CH);         -   M is             -   (i.) a bond; or             -   (ii.) C₁-C₆ alkylene, wherein said C₁-C₆ alkylene of M                 is unsubstituted or substituted by 1 to 6 fluoro;         -   R^(CH) is a ring selected from the group consisting of             -   (i.) C₃-C₉ mono- or bicycloalkyl;             -   (ii.) phenyl; and             -   (iii.) a 3- to 6-membered heterocyclyl, wherein said                 heterocyclyl of R^(CH) is a saturated, partially                 saturated or aromatic ring system containing 1 to 2                 heteroatoms independently selected from the group                 consisting of N, O, and S;             -   wherein R^(CH) is unsubstituted or independently                 substituted by 1 to 4 halo, C₁-C₃ alkyl, C₁-C₃                 trifluoroalkyl, cyano, C₁-C₄ alkylcarbonylamino, or oxo;

Cy is

-   -   (a.) phenyl;     -   (b.) C₃-C₆ cycloalkyl;     -   (c.) a 5- to 9-membered mono- or bicyclic heterocyclyl, wherein         said heterocyclyl of Cy is a saturated, partially saturated, or         aromatic ring system containing 1 to 3 heteroatoms independently         selected from the group consisting of N, O, S and S(O)₂; or     -   wherein Cy is unsubstituted or independently substituted by 1 to         4 R^(k) moieties selected from the group consisting of:         -   (i.) C₁-C₆ alkyl, wherein said C₁-C₆ alkyl is unsubstituted             or independently substituted by 1 to 3 hydroxy or fluoro;         -   (ii.) C₁-C₆ alkoxy, wherein said C₁-C₆ alkoxy is             unsubstituted or independently substituted by 1 to 3 fluoro,             hydroxy, amino, (C₁-C₃ alkyl)amino, di(C₁-C₃ alkyl)amino,             methoxy, or phenyl;         -   (iii.) —N(R^(e1))₂;         -   (iv.) —O(CH₂)_(n4)C(O)N(R^(e1))₂;         -   (v.) —O(CH₂)_(n5)CO₂R^(e1);         -   (vi.) hydroxyl;         -   (vii.) oxo;         -   (viii.) halo;         -   (ix.) C₁-C₃ alkylsulfonyl;         -   (x.) cyano;         -   (xi.) oxetanyl; and         -   (xii.) cyclopropyl;     -   or alternatively, two R^(k) moieties, when substituted on         adjacent ring atoms of Cy, form a second ring, wherein said         second ring is a 5- to 7-membered saturated, partially         saturated, or aromatic ring system that contains 0, 1, or 2         heteroatoms independently selected from the group consisting of         N, O, and S; wherein said second ring is unsubstituted or         substituted by 1 to 3 R^(k) moieties independently selected from         (i)-(xi);         -   each R^(e1) is independently H or C₁-C₃ alkyl;         -   the subscript n4 is 1, 2, or 3;         -   the subscript n5 is 1, 2, or 3;

In embodiment no. 2, the invention provides a compound of Formula (I), wherein

(a.) X¹ is C(R²) and X² is O;

(b.) X¹ is N and X² is O; or

(c.) X¹ is N and X² is CH₂; and

the remaining variables are as described in embodiment no. 1.

In embodiment no. 3, the invention provides a compound of Formula (I), wherein

X¹ is C(R²) and X² is O. and

the remaining variables are as described in embodiment no. 1.

In embodiment no. 4, the invention provides a compound of Formula (I), wherein R³ is other than —C(R^(a))₂N(H)C(O)R^(d), —C(R^(a))₂N(H)S(O)₂R^(d), or —(C(R^(a))₂)₂CO₂R^(c), and the remaining variables are as described in embodiment no. 1.

In embodiment no. 5, the invention provides a compound of Formula (I), wherein R³ is a group of the formula —(C(R^(a))₂)_(n1)N(H)S(O)₂N(R^(b))₂ and the remaining variables are as described in embodiment no. 1.

In embodiment no. 6, the invention provides a compound of Formula (I), wherein R³ is as described in embodiment no. 5, the subscript n1 is 1, and the remaining variables are as described in embodiment no. 1.

In embodiment no. 7, the invention provides a compound of Formula (I), wherein R³ is as described in embodiment no. 5, the subscript n1 is 1, and each R^(b) is independently:

-   -   (i.) H;     -   (ii.) C₁-C₄ alkyl, wherein said C₁-C₄ alkyl is unsubstituted or         substituted by 1 to 3 fluoro;     -   (iii.) —C^(C);     -   alternatively, two R^(b) together with the N atom to which they         are attached form a 5- to 6-membered heterocyclyl, wherein said         heterocyclyl is selected from the group consisting of         pyrrolidinyl, piperidinyl, and morpholinyl; wherein said         heterocyclyl is unsubstituted or substituted by 1 to 2 moieties         independently selected from the group consisting of C₁-C₆ alkyl,         C₁-C₃ alkoxy, fluoro, hydroxyl, oxo, cyano, amino, C₁-C₃         alkylamino, and C₁-C₃ dialkylamino; and     -   ring C^(C) is C₃-C₆ cycloalkyl;         -   wherein ring C^(C) is unsubstituted or independently             substituted by 1 to 2 C₁-C₆ alkyl, C₁-C₃ alkoxy, halo,             hydroxyl, oxo, cyano, amino, C₁-C₃ alkylamino, or C₁-C₃             dialkylamino;             and the remaining variables are as described in embodiment             no. 1.

In embodiment no. 8, the invention provides a compound of Formula (I), wherein Cy is a group of the formula

wherein the subscript s is 0, 1, 2, or 3; and the remaining variables are as described in embodiment no. 1.

In embodiment no. 9, the invention provides a compound of Formula (I), wherein Cy is a group of the formula

wherein the subscript p is 1 or 2; the subscript s is 0, 1, or 2; and the remaining variables are as described in embodiment no. 1.

In embodiment no. 10, the invention provides a compound of Formula (I), wherein Cy is

wherein R^(k1) is C₁-C₆ alkyl or CH₂CH₂OH; R^(k2) is C₁-C₃ alkyl or CHF₂; and the remaining variables are as described in embodiment no. 1.

In embodiment no. 11, the invention provides a compound of Formula (I), wherein Cy is

wherein R^(k2) is C₁-C₃ alkyl or CHF₂; and the remaining variables are as described in embodiment no. 1.

In embodiment no. 12, the invention provides a compound of Formula (I), wherein Cy is a group of the formula:

wherein R^(k1) is C₁-C₆ alkyl or CH₂CH₂OH; and the remaining variables are as described in embodiment no. 1.

In embodiment no. 13, the invention provides a compound of Formula (I), wherein

wherein R^(k3) is C₁-C₃ alkyl or C₁-C₃ fluoroalkyl; and the remaining variables are as described in embodiment no. 1.

In embodiment no. 14, the invention provides a compound of Formula (I), wherein R⁴ is a group of the formula

and the remaining variables are as described in embodiment no. 1.

In embodiment no. 15, the invention provides a compound of Formula (I), wherein R¹ is H or methyl, and the remaining variables are as described in embodiment no. 1.

In embodiment no. 16, the invention provides a compound of Formula (I), wherein:

X¹ and X² are as described in embodiment no. 2;

R¹ is as described in embodiment no. 15;

R² is H;

R³ is as described in embodiment no. 4;

R⁴ is as described in embodiment no. 14; and

Cy is as described in any one of embodiments nos. 8-13.

In embodiment no. 17, the invention provides a compound of Formula (I), wherein:

X¹ and X² are as described in embodiment no. 2;

R¹ is as described in embodiment no. 15;

R² is H;

R³ is as described in embodiment no. 6;

R⁴ is as described in embodiment no. 14; and

Cy is as described in any one of embodiments nos. 8-13.

In embodiment no. 18, the invention provides a compound of Formula (I), wherein R^(b) is as described in embodiment no. 7; and R¹, R², R³, R⁴, and Cy are as described in embodiment no. 17.

In embodiment no. 19, the invention provides a compound of Formula (I), wherein X¹ and X² are as described in embodiment no. 3, and R¹, R², R³, R⁴, and Cy are as described in embodiment no. 16.

In embodiment no. 20, the invention provides a compound of Formula (I), wherein X¹ and X² are as described in embodiment no. 3, and R¹, R², R³, R⁴, and Cy are as described in embodiment no. 17.

In embodiment no. 21, the invention provides a compound of Formula (I), wherein X¹ and X² are as described in embodiment no. 3,

R³ is as described in embodiment no. 7; and R¹, R², R⁴, and Cy are as described in embodiment no. 17.

In embodiment no. 22, the invention provides a compound of Formula (I), wherein Cy is as described in embodiment no. 8;

X¹ and X² are as described in embodiment no. 3; and R¹, R², R³, and R⁴ are as described in embodiment no. 17.

In embodiment no. 23, the invention provides a compound as set forth in any one of embodiment nos. 1-15, wherein R² is H.

In embodiment no. 24, the invention provides a compound as set forth in any one of embodiment nos. 1-23, wherein the compound of Formula (I) has the Formula (IA):

In embodiment no. 25, the invention provides a compound of the Formula (I) wherein;

-   -   X¹ is C(H);     -   X² is CH₂;     -   R¹ is H;     -   R² is H;     -   R³ is:         -   (a.) H;         -   (b.) —CH₂N(H)C(O)CH₃; and         -   (c.) —(CH₂)₃CO₂H;         -   R⁴ is as described in embodiment no. 14;         -   Cy is phenyl, pyrazolyl, or pyridyl, wherein Cy is             unsubstituted or substituted by 1 or 2 R^(k) moieties             selected from the group consisting of C₁-C₃ alkyl, C₁-C₃             alkoxy, trifluoromethyl, halo, and —CH₂CH₂OH.

In embodiment no. 26, the invention provides a compound of the Formula (I) wherein;

-   -   X¹ is N;     -   X² is CH₂;     -   R¹ is H or methyl;     -   R² is H;     -   R³ is:         -   (a.) H;         -   (b.) —N(H)C(O)O—(C₁-C₆ alkyl);         -   (c.) —CH₂OH;         -   (d.) —CH₂S(O)₂CH₂CH₃; or         -   (e.) a group of the formula

-   -   -    which is unsubstituted or substituted by oxo or hydroxyl;

    -   R⁴ is:         -   (a.) C₁-C₈ alkyl, wherein said C₁-C₈ alkyl of R4 is             unsubstituted or substituted by 1 to 3 fluoro; or         -   (b.) —CH₂-phenyl; and

    -   Cy is phenyl or pyrazolyl, wherein Cy is unsubstituted or         substituted by 1 or 2 R^(k) moieties selected from the group         consisting of C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, cyano, and halo.

In embodiment no. 27, the invention provides a compound of the Formula (I) wherein;

-   -   X¹ is C(H);     -   X² is O;     -   R¹ is H;     -   R² is H;     -   R³ is:         -   (a.) —CH₂N(H)S(O)₂N(R^(b))₂; or         -   (b.) a group of the formula

-   -   R^(b) is as set forth in embodiment no. 1;     -   R⁴ is as described in embodiment no. 14;     -   Cy is phenyl or pyrazolyl, wherein Cy is unsubstituted or         substituted by 1 or 2 R^(k) moieties selected from the group         consisting of C₁-C₃ alkyl, C₁-C₃ alkoxy, trifluoromethyl, halo,         and —CH₂CH₂OH.

In embodiment no. 28, the invention provides a compound of the Formula (I) wherein;

-   -   X¹ is C(H);     -   X² is O;     -   R¹ is methyl;     -   R² is H;     -   R³ is:         -   (a.) H;         -   (b.) —C(H)(R^(a))N(H)C(O)OR^(d); or         -   (c.) —CH₂N(H)S(O)₂N(R^(b))₂;         -   R^(b) and R^(d) are as described in embodiment no. 1;     -   R⁴ is as described in embodiment no. 14; and     -   Cy is phenyl or pyrazolyl, wherein Cy is unsubstituted or         substituted by 1 or 2 R^(k) moieties selected from the group         consisting of C₁-C₃ alkyl, C₁-C₃ alkoxy, trifluoromethyl, halo,         and —CH₂CH₂OH.

In embodiment no. 29, the invention provides a compound of the Formula (I) wherein;

-   -   X¹ is C(H);     -   X² is O;     -   R¹ is H;     -   R² is H;     -   R³ is:         -   (a.) —CH₂N(H)C(O)N(R^(b))₂; or         -   (b.) —CH₂N(H)C(O)OR^(d);         -   R^(b) and R^(d) are as described in embodiment no. 1;     -   R⁴ is as described in embodiment no. 14; and     -   Cy is phenyl, pyrazolyl, or pyridyl, wherein Cy is unsubstituted         or substituted by 1 or 2 R^(k) moieties selected from the group         consisting of C₁-C₃ alkyl, C₁-C₃ alkoxy, trifluoromethyl, halo,         and —CH₂CH₂OH.

In embodiment no. 30, the compound is selected from any one of the compounds described in Examples 1-121 (or a pharmaceutically acceptable salt thereof).

In embodiment no. 31, the compound is selected from any one of the following compounds (or a pharmaceutically acceptable salt thereof):

-   (R)-tert-butyl     (2-(hydroxymethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (4-((5-bromo-2-chloropyridin-3-yl)sulfonyl)-2-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-4-((6-((tert-butoxycarbonyl)amino)-2-(hydroxymethyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)sulfonyl)-1-(difluoromethyl)-3-methyl-1H-pyrazol-2-e; -   [(R)-4-((3-chloro-benzenesulfonyl)-2-hydroxymethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic     acid tert-butyl ester; -   (R)-tert-butyl     (4-((5-bromopyridin-3-yl)sulfonyl)-2-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-(hydroxymethyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-(hydroxymethyl)-4-((3-(methylsulfonyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (4-((2-chloro-5-methylpyridin-3-yl)sulfonyl)-2-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (4-((3-cyanophenyl)sulfonyl)-2-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-(hydroxymethyl)-4-((5-methyl-2-oxo-1,2-dihydropyridin-3-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (4-((4-fluorophenyl)sulfonyl)-2-(2-hydroxypropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;     -   (S)-tert-butyl         (4-((4-fluorophenyl)sulfonyl)-2-(2-hydroxypropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl     4-(3,4-difluorophenylsulfonyl)-2-(2,2,2-trifluoroacetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylcarbamate; -   (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2,2,2-trifluoroacetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(((benzyloxy)carbonyl)aminomethyl)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((4-fluorophenyl)sulfonyl)-2-((3-(tetrahydro-2H-pyran-4-yl)ureido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(((benzyloxy)carbonyl)aminomethyl)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(((benzyloxy)carbonyl)aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(((methoxy)carbonyl)aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-((3-cyclopropylureido)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-((3-cyclobutylureido)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-((3-(tert-butyl)ureido)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((4-fluorophenyl)sulfonyl)-2-((3-isopropylureido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-((3-(thiophen-3-yl)ureido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-((3-ethylureido)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-((3-cyclohexylureido)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((4-fluorophenyl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((4-fluorophenyl)sulfonyl)-2-((morpholine-4-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(((N,N-diethylsulfamoyl)amino)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(((N,N-dimethylsulfamoyl)amino)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-((piperidine-1-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-((pyrrolidine-1-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     ((2S)-4-((4-fluorophenyl)sulfonyl)-2-((2-methylpiperidine-1-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl((2S)-2-((2,6-dimethylmorpholine-4-sulfonamido)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((4-fluorophenyl)sulfonyl)-2-((4-methylpiperidine-1-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl((2S)-4-((4-fluorophenyl)sulfonyl)-2-((2-methylmorpholine-4-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(((N-cyclopropyl-N-methylsulfamoyl)amino)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(((N-cyclopentyl-N-methylsulfamoyl)amino)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((4-fluorophenyl)sulfonyl)-2-((N-methyl-N-(2,2,2-trifluoroethyl)sulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((piperidine-1-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl((2S)-4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(2-methylpiperidine-1-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl((2S)-4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((2-methylmorpholine-4-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((N-methyl-N-(2,2,2-trifluoroethyl)sulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((N-isobutyl-N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl((2S)-4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((3-methylpyrrolidine-1-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((N-ethylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((N-isopropylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(((N-ethylsulfamoyl)amino)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-((N-isopropylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-((N-(tert-butyl)sulfamoyl)amino)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((3,4-difluorophenyl)sulfonyl)-2-((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((1-ethyl-3-methyl-1H-pyrazol-4-yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((3-(2,2-difluoroethoxy)-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((1-(2,2-difluoroethyl)-3-ethoxy-1H-pyrazol-4-yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((2-methoxy-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-((pyridin-2-ylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-((cyclopentylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-((benzylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-((tert-butylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-(((4,5-dimethyl-1H-imidazol-2-yl)thio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-((phenylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-((methylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-((pyridin-2-ylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-((tert-butylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-(((4,5-dimethyl-1H-imidazol-2-yl)sulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-((phenylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-((cyclopentylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-((benzylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-((methylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-((pyridin-2-ylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-((N-cyclopropylsulfamoyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-((N-(2,2,2-trifluoroethyl)sulfamoyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-((morpholinosulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-((N-ethylsulfamoyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-((N,N-dimethylsulfamoyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     (S)-(4-((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   [(2S,3S and     2R,3R)-4-(3-cyano-benzenesulfonyl)-2-hydroxymethyl-3-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic     acid 2,2-dimethyl-propyl ester; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((4-fluorophenyl)sulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-3-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((4-fluorophenyl)sulfonyl)-3-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   [(S)-4-(3-cyano-benzenesulfonyl)-2-(2,4-dioxo-oxazolidin-3-ylmethyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic     acid tert-butyl ester; -   (1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl     ((S)-4-((3-cyanophenyl)sulfonyl)-2-((2,4-dioxooxazolidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-neopentyl     (4-((3-cyanophenyl)sulfonyl)-2-((2,4-dioxooxazolidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (1S,4R)-bicyclo[2.2.1]heptan-2-yl((S)-2-((2,4-dioxooxazolidin-3-yl)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-((2,4-dioxooxazolidin-3-yl)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-neopentyl     (2-((2,4-dioxooxazolidin-3-yl)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;     (tetrahydro-2H-pyran-2-yl)methyl     ((S)-2-((2,4-dioxooxazolidin-3-yl)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (2S)-bicyclo[2.2.1]heptan-2-yl((S)-4-((3-cyanophenyl)sulfonyl)-2-((2,4-dioxooxazolidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (2S)-bicyclo[2.2.1]heptan-2-yl((S)-2-((2,4-dioxooxazolidin-3-yl)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   [(S)-4-(3-cyano-benzenesulfonyl)-2-dimethylaminomethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic     acid tert-butyl ester; -   [(S)-4-(3-cyano-benzenesulfonyl)-2-dimethylaminomethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic     acid 2,2-dimethyl-propyl ester; -   (1S,4R)-bicyclo[2.2.1]heptan-2-yl((S)-4-((3-cyanophenyl)sulfonyl)-2-((dimethylamino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl((S)-4-((3-cyanophenyl)sulfonyl)-2-((dimethylamino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-neopentyl     (2-((dimethylamino)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   bicyclo[2.2.1]heptan-2-yl     ((S)-2-((dimethylamino)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (2S)-bicyclo[2.2.1]heptan-2-yl     ((S)-2-((dimethylamino)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tetrahydro-2H-pyran-4-yl(4-((3-cyanophenyl)sulfonyl)-2-((dimethylamino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-methyl     2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate; -   (S)-methyl     2-(6-((tert-butoxycarbonyl)amino)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate; -   (S)-methyl     2-(6-((tert-butoxycarbonyl)amino)-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate; -   (S)-methyl     2-(6-((tert-butoxycarbonyl)amino)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate; -   (R)-methyl     2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate; -   (S)-methyl     2-(4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate; -   [(S)-6-tert-butoxycarbonylamino-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl]-acetic     acid; -   (S)-2-(6-((tert-butoxycarbonyl)amino)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic     acid; -   (S)-2-(6-((tert-butoxycarbonyl)amino)-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic     acid; -   (S)-2-(6-((tert-butoxycarbonyl)amino)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic     acid; -   (S)-2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic     acid; -   (S)-2-(6-((tert-butoxycarbonyl)amino)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic     acid; -   (S)-2-(4-((4-fluorophenyl)sulfonyl)-6-(((neopentyloxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic     acid; -   (S)-2-(6-((tert-butoxycarbonyl)amino)-4-((3-chlorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic     acid; -   (S)-2-(4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic     acid; -   (R)-6-((tert-butoxycarbonyl)amino)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic     acid; -   (R)-6-((tert-butoxycarbonyl)amino)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic     acid; -   (R)-6-((tert-butoxycarbonyl)amino)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic     acid; -   (R)-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic     acid; -   (R)-6-((tert-butoxycarbonyl)amino)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic     acid; -   (R)-6-((tert-butoxycarbonyl)amino)-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic     acid; -   [(S)-2-(2-azetidin-1-yl-2-oxo-ethyl)-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic     acid tert-butyl ester; -   [(S)-2-(2-azetidin-1-yl-2-oxo-ethyl)-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic     acid 1,2,2-trimethyl-propyl ester; -   (S)-tert-butyl     (2-(2-amino-2-oxoethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-amino-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (4-((4-fluorophenyl)sulfonyl)-2-(2-(methylamino)-2-oxoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(methylamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(dimethylamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   tert-butyl     (2-(2-(dimethylamino)-2-oxoethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(2-(methylamino)-2-oxoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(2-(methylamino)-2-oxoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(2-(methylamino)-2-oxoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-(2-(oxazolidin-3-yl)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-((cyclobutylmethyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-oxo-2-(3,3,3-trifluoropropyl)amino)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(isobutylamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(((1H-pyrazol-4-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(((1H-pyrazol-3-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(((1-isopropyl-1H-pyrazol-4-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-oxo-2-((pyrazolo[1,5-a]pyridin-3-ylmethyl)amino)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(((1-ethyl-1H-pyrazol-3-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(1-methylpyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(((1-methyl-1H-pyrazol-3-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(((1-ethyl-1H-pyrazol-4-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(((1-ethyl-5-methyl-1H-pyrazol-4-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(((1,5-dimethyl-1H-pyrazol-4-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate -   (S)-tert-butyl     (2-(2-(((1-benzyl-1H-pyrazol-4-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-3-(2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetamido)propanoic     acid -   (S)-methyl     3-(2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetamido)propanoate; -   (S)-tert-butyl     (2-(2-oxo-2-((4-(trifluoromethyl)benzyl)amino)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(benzylamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-((cyclopropylmethyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-oxo-2-(propylamino)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(ethylamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(oxazolidin-3-yl)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-neopentyl     (2-(2-(methylamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(((2H-tetrazol-5-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-((2-hydroxyethyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(tert-butylamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   tert-butyl     ((2S)-2-(2-(2-methylazetidin-1-yl)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(3-cyanoazetidin-1-yl)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(3-methoxyazetidin-1-yl)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(azetidin-1-yl)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(azetidin-1-yl)-2-oxoethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(3-methylazetidin-1-yl)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-neopentyl     (2-(2-(azetidin-1-yl)-2-oxoethyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-carbamoyl-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-carbamoyl-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-carbamoyl-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-methyl     3-(6-((tert-butoxycarbonyl)amino)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamido)propanoate; -   (R)-tert-butyl     (2-carbamoyl-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-2-(dimethylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-3-(6-((tert-butoxycarbonyl)amino)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamido)propanoic     acid; -   tert-butyl     (2-(2-cyanopropan-2-yl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R and S)     2-(4-((4-fluorophenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanoic     acid; -   (R and     S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-(2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-oxo-2-(trifluoromethylsulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-neopentyl     (2-(2-(cyclopropanesulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-neopentyl     (4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-oxo-2-(trifluoromethylsulfonamido)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-oxo-2-(thiazole-2-sulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-oxo-2-(pyridine-4-sulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(1,1-dimethylethylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-oxo-2-(5-(trifluoromethyl)pyridine-2-sulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-neopentyl     (4-((4-fluorophenyl)sulfonyl)-2-(2-oxo-2-(trifluoromethylsulfonamido)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-oxo-2-(pyridine-2-sulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-oxo-2-(pyridine-3-sulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-oxo-2-(4-(trifluoromethyl)pyridine-2-sulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-oxo-2-(1H-pyrazole-4-sulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(4-methylpyridine-2-sulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(2-fluoro-5-methylphenylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(2-fluorophenylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-oxo-2-(2-(trifluoromethyl)phenylsulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-oxo-2-(3-(trifluoromethyl)phenylsulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(3-fluorophenylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(cyclopropanesulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(4-methylphenylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(1-methylethylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(ethylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(methylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-neopentyl     (2-(2-(cyclopropanesulfonamido)-2-oxoethyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(cyclopentanesulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(2-methylphenylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(4-fluorophenylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(2,5-dimethylphenylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-oxo-2-(4-propylphenylsulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(6-methylpyridine-2-sulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-neopentyl     (2-(2-(cyclopropanesulfonamido)-2-oxoethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-(2-(2-(methoxyamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamic     acid; -   (S)-tert-butyl     (2-(2-oxo-2-((2-(trifluoromethyl)phenoxy)amino)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-oxo-2-((pyridin-3-ylmethoxy)amino)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-oxo-2-(((4-(trifluoromethyl)benzyl)oxy)amino)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-oxo-2-(((3-(trifluoromethyl)benzyl)oxy)amino)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-((4-fluorophenoxy)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-((cyclopentyloxy)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(ethoxyamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-((benzyloxy)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(((4-methylbenzyl)oxy)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(isopropoxyamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-oxo-2-(propoxyamino)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (4-((4-fluorophenyl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((4-fluorophenyl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (4-((4-fluorophenyl)sulfonyl)-2-((4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-2-((4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-((4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (4-((4-fluorophenyl)sulfonyl)-2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   tert-butyl     (2-(cyanomethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   tert-butyl     (2-(2-hydroxypropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-amino-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)     sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-acetamido-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-propionamidoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   tert-butyl     ((2S)-2-(2-(2-hydroxypropanamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(oxetane-3-carboxamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-isobutyramidoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-acetamidoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(cyclopropanecarboxamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (4-((4-fluorophenyl)sulfonyl)-2-(2-propionamidoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-acetamidoethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   tert-butyl     ((2S)-4-((4-fluorophenyl)sulfonyl)-2-(2-(2-hydroxypropanamido)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(cyclopropanecarboxamido)ethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-neopentyl     (4-((4-fluorophenyl)sulfonyl)-2-(2-propionamidoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-neopentyl     (2-(2-acetamidoethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-neopentyl     (2-(2-(cyclopropanecarboxamido)ethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(2-amino-2-methylpropyl)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(2-amino-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-acetamido-2-methylpropyl)-4-((3-chloro-4-fluorophenyl)     sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-acetamido-2-methylpropyl)-4-((3,4-difluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-acetamido-2-methylpropyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-acetamido-2-methylpropyl)-4-((1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-acetamido-2-methylpropyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-(2-acetamido-2-methylpropyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(2-acetamido-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(2-acetamido-2-methylpropyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(2-acetamido-2-methylpropyl)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(2-acetamido-2-methylpropyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((4-fluorophenyl)sulfonyl)-2-(2-methyl-2-(methylsulfonamido)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(2-acetamido-2-methylpropyl)-4-((3,4-difluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(2-methyl-2-(methylsulfonamido)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((3,4-difluorophenyl)sulfonyl)-2-(2-methyl-2-(methylsulfonamido)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(2-(cyclopropanesulfonamido)-2-methylpropyl)-4-((3,4-difluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(2-methyl-2-(methylsulfonamido)propyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(2-(cyclopropanesulfonamido)-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(2-methyl-2-(methylsulfonamido)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(2-(cyclopropanesulfonamido)-2-methylpropyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(cyclopropanesulfonamido)-2-methylpropyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(2-methyl-2-(trifluoromethylsulfonamido)propyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(2-(2-(dimethylamino)-2-oxoacetamido)-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(2-acetamido-2-methylpropyl)-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-acetamido-2-methylpropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(2-acetamido-2-methylpropyl)-4-((3-methoxy-1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(2-acetamido-2-methylpropyl)-4-((1-(difluoromethyl)-3-ethoxy-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(2-acetamido-2-methylpropyl)-4-((3-(difluoromethoxy)-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   tert-butyl     (2-(2-hydroxyethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   tert-butyl     (2-((1H-imidazol-2-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   tert-butyl     (2-((1-methyl-1H-imidazol-2-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (4-((4-fluorophenyl)sulfonyl)-2-((2-oxopyrrolidin-1-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-((1H-pyrazol-1-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-((2H-1,2,3-triazol-2-yl)methyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-((4H-1,2,4-triazol-4-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-((1H-1,2,4-triazol-1-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-((1H-1,2,3-triazol-1-yl)methyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-((1H-1,2,3-triazol-1-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-((2H-1,2,3-triazol-2-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-tert-butyl     (2-((pyridin-2-yloxy)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-((2-oxopyridin-1(2H)-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-((5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   tert-butyl     (2-(2-hydroxy-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-((3-hydroxyazetidin-1-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(((3-methyloxetan-3-yl)amino)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   tert-butyl     ((2S)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-2-(((1,1,1-trifluoropropan-2-yl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl((2S)-4-((4-fluorophenyl)sulfonyl)-2-(2-methylazetidin-1-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((4-fluorophenyl)sulfonyl)-2-(3-hydroxyazetidin-1-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(azetidin-1-ylmethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)carbamate; -   [(R)-1-((3-chloro-benzenesulfonyl)-3-hydroxymethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl]-carbamic     acid tert-butyl ester; -   [(S)-1-(3-chloro-benzenesulfonyl)-3-(2,4-dioxo-oxazolidin-3-ylmethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl]-carbamic     acid tert-butyl ester; -   4-[(S)-6-amino-4-((3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl]-1-methyl-piperazin-2-one; -   (S)-tert-butyl     (5-((4-fluorophenyl)sulfonyl)-6-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate; -   (S)-benzyl tert-butyl     (1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate; -   benzyl tert-butyl     (1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate; -   benzyl tert-butyl     (1-((3-cyanophenyl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate; -   benzyl tert-butyl     (1-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate; -   (S)-benzyl     (5-((4-fluorophenyl)sulfonyl)-7-(2-oxopyrrolidin-1-yl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate; -   (S)-neopentyl     (5-((4-fluorophenyl)sulfonyl)-7-(2-oxopyrrolidin-1-yl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate; -   (R)-neopentyl     (5-((4-fluorophenyl)sulfonyl)-7-(2-oxopyrrolidin-1-yl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate; -   tert-butyl     (5-((4-fluorophenyl)sulfonyl)-7-hydroxy-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate; -   (R)-neopentyl     (5-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-7-(hydroxymethyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate; -   (S)-neopentyl     (5-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-7-(hydroxymethyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate; -   tert-butyl     (7-(hydroxymethyl)-5-(m-tolylsulfonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate; -   tert-butyl     (5-((3,4-difluorophenyl)sulfonyl)-7-(hydroxymethyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate; -   (R or S)-neopentyl     (5-((4-fluorophenyl)sulfonyl)-7-(hydroxymethyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate; -   (S or R)-neopentyl     (5-((4-fluorophenyl)sulfonyl)-7-(hydroxymethyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate; -   neopentyl     ((S)-5-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     (4-((4-fluorophenyl)sulfonyl)-2-(2,2,2-trifluoroacetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   2,2,2-trifluoro-1,1-dimethylethyl     [(2S)-4-{[1-(difluoromethyl)-3-(2-hydroxyethoxy)-1H-pyrazol-4-yl]sulfonyl}-2-{[(methylsulfamoyl)amino]methyl}-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate; -   2,2,2-trifluoro-1,1-dimethylethyl     [(2S)-2-[2-(acetylamino)-2-methylpropyl]-4-{[1-ethyl-3-(2-hydroxyethoxy)-1H-pyrazol-4-yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     ((R)-4-((3,4-difluorophenyl)sulfonyl)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     ((S)-4-((3,4-difluorophenyl)sulfonyl)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     ((R)-4-((3,4-difluorophenyl)sulfonyl)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     ((S)-4-((3,4-difluorophenyl)sulfonyl)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     ((R)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     ((R)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     ((S)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     ((R)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     (4-((4-fluorophenyl)sulfonyl)-2-(2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     ((S)-2-((R)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     ((S)-2-((S)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     ((R)-2-((R)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     ((R)-2-((S)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (2-(2-(ethylsulfonyl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(2-(ethylsulfonyl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     ((2S,3R)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3-methyl-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     N-[(2S,3R)-2-[(1S)-1-[[(benzyloxy)carbonyl]amino]ethyl]-4-[(3,4-difluorobenzene)sulfonyl]-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     (3-(acetamidomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-carbamoylcyclopropyl)methyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-carbamoylcyclopropyl)methyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     ((S)-2-((R)-3-amino-2-cyclopropyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     ((S)-2-((S)-3-amino-2-cyclopropyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   2,2,2-trifluoro-1,1-dimethylethyl     {(2S)-2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-[(4-fluoro-3-methoxyphenyl)sulfonyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((S)-3-amino-2-cyclopropyl-3-oxopropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((S)-3-amino-2-cyclopropyl-3-oxopropyl)-4-((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((R)-3-amino-2-cyclopropyl-3-oxopropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     ((S)-2-((R)-3-amino-2-cyclopropyl-3-oxopropyl)-4-((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   2,2,2-trifluoro-1,1-dimethylethyl     [(2S)-2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-{[5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate; -   2,2,2-trifluoro-1,1-dimethylethyl     {2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-[(3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbamate; -   2,2,2-trifluoro-1,1-dimethylethyl     [2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-{[1-ethyl-3-(2-hydroxyethoxy)-1H-pyrazol-4-yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate; -   (S)-methyl     2-((4-((2-(3-amino-2,2-dimethyl-3-oxopropyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-2H-benzo[b][1,4]oxazin-4(3H)-yl)sulfonyl)-1-ethyl-1H-pyrazol-3-yl)oxy)acetate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyanoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((1-cyanocyclopropyl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((1-cyanocyclopropyl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-cyano-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-cyano-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyano-2-methylpropyl)-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyano-2-methylpropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(2-cyano-2-methylpropyl)-4-((4-fluoro-3-methylphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(2-cyano-2-methylpropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyano-2-methylpropyl)-4-((4-fluoro-3-methylphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyano-2-methylpropyl)-4-((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(2-cyano-2-methylpropyl)-4-((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(3-(cyclopropanesulfonamido)-3-oxopropyl)-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     ((S)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((S)-3-(cyclopropanesulfonamido)-2-methyl-3-oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     ((S)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((R)-3-(cyclopropanesulfonamido)-2-methyl-3-oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   2,2,2-trifluoro-1,1-dimethylethyl     [(2S)-2-{3-[(tert-butylsulfonyl)amino]-3-oxopropyl}-4-{[4-fluoro-3-(trifluoromethyl)phenyl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate; -   2,2,2-trifluoro-1,1-dimethylethyl     [(2S)-4-{[4-fluoro-3-(trifluoromethyl)phenyl]sulfonyl}-2-(3-{[(4-methylphenyl)sulfonyl]amino}-3-oxopropyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate; -   2,2,2-trifluoro-1,1-dimethylethyl     [(2S)-4-{[4-fluoro-3-(trifluoromethyl)phenyl]sulfonyl}-2-(3-oxo-3-{[(trifluoromethyl)sulfonyl]amino}propyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl ((S)-2-((R and     S)-3-(cyclopropanesulfonamido)-2-methyl-3-oxopropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     ((S)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((R)-3-(1,1-dimethylethylsulfonamido)-2-methyl-3-oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((R)-3-(cyclopropanesulfonamido)-2-methyl-3-oxopropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((R)-3-(1,1-dimethylethylsulfonamido)-2-methyl-3-oxopropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((S)-3-(cyclopropanesulfonamido)-2-methyl-3-oxopropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     ((S)-2-((S)-3-(1,1-dimethylethylsulfonamido)-2-methyl-3-oxopropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   1,1,1-trifluoro-2-methylpropan-2-yl     ((S)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((S)-3-(1,1-dimethylethylsulfonamido)-2-methyl-3-oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-2-(oxetan-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (2-(2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   2,2,2-trifluoro-1,1-dimethylethyl     [(2S)-2-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl]-4-{[3-(trifluoromethyl)phenyl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate; -   2,2,2-trifluoro-1,1-dimethylethyl     {(2S)-4-[(3-cyclopropylphenyl)sulfonyl]-2-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbamate; -   tert-butyl     {(2S)-4-[(3-cyclopropylphenyl)sulfonyl]-2-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-tert-butyl     (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((4-fluoro-3-methoxyphenyl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluoro-3-methoxyphenyl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   2,2,2-trifluoro-1,1-dimethylethyl     {(2S)-4-[(3-cyclopropylphenyl)sulfonyl]-2-[2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbamate; -   2,2,2-trifluoro-1,1-dimethylethyl     {(2S)-4-[(4-fluoro-3-methoxyphenyl)sulfonyl]-2-[2-methyl-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(1H-tetrazol-5-yl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   2,2,2-trifluoro-1,1-dimethylethyl     {(2S)-4-[(3-cyclopropylphenyl)sulfonyl]-2-[2-(1H-tetrazol-5-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbamate; -   2,2,2-trifluoro-1,1-dimethylethyl     [(2S)-2-[2-(1H-tetrazol-5-yl)ethyl]-4-{[2-(trifluoromethyl)pyridin-4-yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(1H-tetrazol-5-yl)ethyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-1,1,1-trifluoro-2-methylpropan-2-yl(24     hydroxymethyl)-5-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate; -   (R)-1,1,1-trifluoro-2-methylpropan-2-yl(5-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(5-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate; -   (S)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoic     acid; -   (R)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoic     acid; -   1,1,1-trifluoro-2-methylpropan-2-yl     (1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate; -   2,2,2-trifluoro-1,1-dimethylethyl     {1-[(3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl]-1,2,3,4-tetrahydroquinolin-7-yl}carbamate; -   2,2,2-trifluoro-1,1-dimethylethyl     (1-{[1-ethyl-3-(2-hydroxyethoxy)-1H-pyrazol-4-yl]sulfonyl}-1,2,3,4-tetrahydroquinolin-7-yl)carbamate; -   2,2,2-trifluoro-1,1-dimethylethyl     {1-[(3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl]-1,2,3,4-tetrahydroquinolin-7-yl}carbamate; -   2,2,2-trifluoro-1,1-dimethylethyl     (1-{[2-(trifluoromethyl)pyridin-4-yl]sulfonyl}-1,2,3,4-tetrahydroquinolin-7-yl)carbamate; -   (R)-1,1,1-trifluoro-2-methylpropan-2-yl     (3-(acetamidomethyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate; -   (S)-1,1,1-trifluoro-2-methylpropan-2-yl     (3-(acetamidomethyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate; -   (R)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic     acid; -   (S)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic     acid; -   (R)-3-(7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1-((5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic     acid; -   (R)-3-(1-((4-fluoro-3-methoxyphenyl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic     acid; -   (S)-3-(7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1-((5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic     acid; -   (S)-3-(1-((4-fluoro-3-methoxyphenyl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic     acid; -   1,1,1-trifluoro-2-methylpropan-2-yl     (5-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-8-oxo-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;     and -   1,1,1-trifluoro-2-methylpropan-2-yl     (1-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-4-oxo-1,2,3,4-tetrahydroquinolin-7-yl)carbamate.

The invention also provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof in purified form.

Uses of the Compounds

Compounds of Formula (I) alter the interaction of coregulator proteins with Retinoic Acid Receptor-related Orphan Receptor gamma t (RORgammaT) and thereby antagonize RORgammaT-mediated transcriptional activity, and as such are useful in the treatment of diseases and conditions in which inhibition of RORgammaT is desirable, such as autoimmune and inflammatory diseases and disorders.

Accordingly, another embodiment of the present invention provides a method for treating a disease or condition mediated by RORgammaT in a subject comprising administering to the subject an amount of a compound of Formula (I) that is effective for treating the disease or condition mediated by RORgammaT in the subject.

The compounds according to the invention can be used in therapy.

A further aspect of the invention resides in the use of compounds of Formula (I) for the treatment of RORgammaT-mediated diseases or RORgammaT-mediated conditions.

Another aspect of the invention resides in the use of a compound of Formula (I) in the manufacture of a medicament for the treatment of a disease or condition mediated by RORgammaT.

Another aspect of the invention resides in the use of compounds of Formula (I) for the treatment of autoimmune diseases, in particular those diseases in which Th17 cells and non-Th17 cells, which express Th17 hallmark cytokines, play a prominent role. These include, but are not limited to, the treatment of rheumatoid arthritis, psoriasis, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), ankylosing spondylitis, and multiple sclerosis.

In another aspect, compounds of Formula (I) can be used for treatment of inflammatory diseases in which Th17 cells and/or non-Th17 cells, which express Th17 hallmark cytokines, play a prominent role, such as but not limited to respiratory diseases, osteoarthritis, and asthma. Also, compounds of Formula (I) can be used for treatment of infectious diseases in which Th17 cells and/or non-Th17 cells, which express Th17 hallmark cytokines, play a prominent role, such as but not limited to mucosal leishmaniasis.

In another aspect, compounds of Formula (I) can be used in the treatment of cancer. Those skilled in the art will recognize the term “cancer” to be a name for diseases in which the body's cells become abnormal and divide without control. The term cancer includes, but is not limited to, colorectal, lung, and pancreatic cancer.

Compounds of Formula (I) can also be used for treatment of other diseases in which Th17 cells and/or non-Th17 cells, which express Th17 hallmark cytokines, play a prominent role, such as but not limited to Kawasaki disease and Hashimoto's thyroiditis.

In one aspect, the disease or condition is an autoimmune disease or inflammatory disease. The disease or condition includes, but is not limited to, multiple sclerosis, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), psoriasis, rheumatoid arthritis, asthma, osteoarthritis, Kawasaki disease, Hashimoto's thyroiditis, and mucosal leishmaniasis.

In another aspect, the compounds of Formula (I) can be used in therapies to treat or prevent multiple sclerosis, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), psoriasis, rheumatoid arthritis, asthma, osteoarthritis, Kawasaki disease, Hashimoto's thyroiditis, and mucosal leishmaniasis.

In another aspect, the compounds of Formula (I) can be used to treat or prevent psoriasis.

In yet another aspect, the compounds of Formula (I) can be used to treat inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).

In another aspect, the compound of Formula (I) can be used to treat colorectal cancer.

In another aspect, the compound of Formula (I) can be used to treat lung cancer.

In another aspect, the compound of Formula (I) can be used to treat pancreatic cancer.

Route of Administration/Dosage

The compounds of this invention can be administered for the treatment or prevention of afflictions, diseases, and illnesses according to the invention by any means that effects contact of the active ingredient compound with the site of action in the body of a warm-blooded animal. For example, administration can be oral, topical, including transdermal, ocular, buccal, intranasal, inhalation, intravaginal, rectal, intracisternal, and parenteral. The term “parenteral” as used herein refers to modes of administration that include subcutaneous, intravenous, intramuscular, intraarticular injection or infusion, intrasternal and intraperitoneal. For the purpose of this disclosure, a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes mammals and birds.

The compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage administered will be dependent on the age, health, and weight of the recipient; the extent of disease; kind of concurrent treatment, if any; frequency of treatment; and the nature of the effect desired. Usually, a daily dosage of active ingredient compound will be from about 1.0-2000 milligrams per day. Ordinarily, from 10 to 500 milligrams per day in one or more applications is effective to obtain desired results. These dosages are the effective amounts for the treatment and prevention of afflictions, diseases, and illnesses described above, e.g., autoimmune and inflammatory diseases and disorders.

Compositions include those suitable for oral, sublingual, subcutaneous, intravenous, intramuscular, nasal, local, or rectal administration, and the like, all in unit dosage forms for administration.

For oral administration, the active ingredient may be presented as discrete units, such as tablets, capsules, powders, granulates, solutions, suspensions, and the like.

For parenteral administration, the pharmaceutical composition of the invention may be presented in unit-dose or multi-dose containers, e.g., injection liquids in predetermined amounts, for example in sealed vials and ampoules, and may also be stored in a freeze dried (lyophilized) condition requiring only the addition of sterile liquid carrier, e.g., water, prior to use.

Mixed with such pharmaceutically acceptable auxiliaries, e.g., as described in the standard reference, Gennaro, A. R. et al., Remington: The Science and Practice of Pharmacy (20th Edition., Lippincott Williams & Wilkins, 2000, see especially Part 5: Pharmaceutical Manufacturing), the active agent may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories. By means of pharmaceutically acceptable liquids the active agent can be applied as a fluid composition, e.g., as an injection preparation, in the form of a solution, suspension, emulsion, or as a spray, e.g., a nasal spray.

For making solid dosage units, the use of conventional additives such as fillers, colorants, polymeric binders, and the like is contemplated. In general any pharmaceutically acceptable additive that does not interfere with the function of the active compounds can be used. Suitable carriers with which the active agent of the invention can be administered as solid compositions include lactose, starch, cellulose derivatives, and the like, or mixtures thereof, used in suitable amounts. For parenteral administration, aqueous suspensions, isotonic saline solutions, and sterile injectable solutions may be used, containing pharmaceutically acceptable dispersing agents and/or wetting agents, such as propylene glycol or butylene glycol.

Pharmaceutical Compositions

Another aspect of the present invention provides pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The term “excipient” and “carrier” may be used interchangeably. The term “composition,” as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product that results, directly or indirectly, from combination, complexation, or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of Formula (I), additional active ingredient(s), and pharmaceutically acceptable excipients.

The pharmaceutical compositions of the present invention comprise a compound represented by Formula (I) (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants.

The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy in light of the present disclosure.

The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, troches, dragées, granules, and powders, or in liquid dosage forms, such as elixirs, syrups, emulsions, dispersions, and suspensions. The active ingredient can also be administered parenterally, in sterile liquid dosage forms, such as dispersions, suspensions, or solutions. Other dosages forms that can also be used to administer the active ingredient as an ointment, cream, drops, transdermal patch, or powder for topical administration, as an ophthalmic solution or suspension formation, i.e., eye drops, for ocular administration, as an aerosol spray or powder composition for inhalation or intranasal administration, or as a cream, ointment, spray, or suppository for rectal or vaginal administration.

Gelatin capsules can contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours, for example. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propylparaben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field.

For administration by inhalation, the compounds of Formula (I) may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulizers. The compounds may also be delivered as powders which may be formulated and the powder composition may be inhaled with the aid of an insufflation powder inhaler device. The preferred delivery system for inhalation is a metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of a compound of Formula (I) in suitable propellants, such as fluorocarbons or hydrocarbons.

For ocular administration, an ophthalmic preparation may be formulated with an appropriate weight percent solution or suspension of the compounds of Formula (I) in an appropriate ophthalmic vehicle, such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the corneal and internal regions of the eye.

Useful pharmaceutical dosage forms for administration of the compounds of this invention include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral injectables, and oral suspensions.

A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.

A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil, or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried.

A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol. The solution is made to volume with water for injection and sterilized.

An aqueous suspension is prepared for oral administration so that each 5 milliliters contains 100 milligrams of finely divided active ingredient, 100 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 milliliters of vanillin.

The same dosage forms can generally be used when the compounds of this invention are administered stepwise or in conjunction with another therapeutic agent. When drugs are administered in physical combination, the dosage form and administration route should be selected depending on the compatibility of the combined drugs. Thus the term “coadministration” is understood to include the administration of the two agents concomitantly or sequentially, or alternatively as a fixed dose combination of the two active components.

The present invention also relates to a pharmaceutical composition comprising compounds of Formula (I) or pharmaceutically acceptable salts thereof in admixture with pharmaceutically acceptable auxiliaries and optionally other therapeutic agents. The auxiliaries must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.

The invention further includes a pharmaceutical composition, as hereinbefore described, in combination with packaging material suitable for said composition, said packaging material including instructions for the use of the composition for the use as hereinbefore described.

The exact dose and regimen of administration of the active ingredient, or a pharmaceutical composition thereof, may vary with the particular compound, the route of administration, and the age and condition of the individual subject to whom the medicament is to be administered.

In general, parenteral administration requires lower dosages than other methods of administration which are more dependent upon absorption. However, a dosage for humans preferably contains 0.0001-100 mg per kg body weight. The desired dose may be presented as one dose or as multiple subdoses administered at appropriate intervals throughout the day. The dosage as well as the regimen of administration may differ between a female and a male recipient.

Combination Therapy

Compounds of Formula (I), and pharmaceutically acceptable salts and physiologically functional derivatives (e.g., prodrugs) thereof, may be employed alone or in combination with other therapeutic agents for the treatment of diseases and conditions associated with inappropriate IL-17 pathway activity. Combination therapies according to the present invention thus comprise the administration of at least one compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a physiologically functional derivative thereof, and the use of at least one other pharmaceutically active agent. The compound(s) of Formula (I) and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, this may occur simultaneously or sequentially in any order. The amounts of the compound(s) of Formula (I) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.

For the treatment of the inflammatory and autoimmune diseases, rheumatoid arthritis, psoriasis, inflammatory bowel disease, ankylosing spondylitis, SLE (systemic lupus erythematosus), uveitis, atopic dermatitis, COPD, asthma, and allergic rhinitis, a compound of Formula (I) may be combined with one or more other active agents such as: (1) TNF-a inhibitors; (2) non-selective COX-1/COX-2 inhibitors; (3) COX-2 inhibitors; (4) other agents for treatment of inflammatory and autoimmune diseases including glucocorticoids, methotrexate, leflunomide, sulfasalazine, azathioprine, cyclosporin, tacrolimus, penicillamine, bucillamine, actarit, mizoribine, lobenzarit, ciclesonide, hydroxychloroquine, d-penicillamine, aurothiomalate, auranofin or parenteral or oral gold, cyclophosphamide, Lymphostat-B, BAFF/APRIL inhibitors and CTLA-4-Ig or mimetics thereof; (5) leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist; (6) LTD4 receptor antagonist; (7) PDE4 inhibitor; (8) antihistamine HI receptor antagonists; (9) a1- and a2-adrenoceptor agonist; (10) anticholinergic agents; (11) β-adrenoceptor agonists; (12) insulin-like growth factor type I (IGF-1) mimetic; (13) glucocorticosteroids; (14) kinase inhibitors such as inhibitors of the Janus Kinases (JAK1 and/or JAK2 and/or JAK3 and/or TYK2), p38 MAPK and IKK2; (15) B-cell targeting biologics such as rituximab; (16) selective costimulation modulators such as abatacept; (17) interleukin inhibitors, such as IL-1 inhibitor anakinra, IL-6 inhibitor tocilizumab, and IL12/IL-23 inhibitor ustekinumab. The compound of Formula (I) may also be combined with anti-IL17 antibodies to obtain additive/synergistic responses for the treatment of inflammatory and autoimmune diseases.

For the treatment of cancer, the compounds of Formula (I) can be combined with other therapeutic, chemotherapeutic, and anti-cancer agents. Combinations of the compounds of Formula (I) with other therapeutic, chemotherapeutic, and anti-cancer agents are within the scope of the invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V. T. Devita and S. Hellman (editors), 6^(th) edition (Feb. 15, 2001), Lippincott Williams & Wilkins Publishers. In light of the present disclosure, a person of ordinary skill in the art would be able to discern which combinations of the compounds of Formula (I) with the other therapeutic, chemotherapeutic, and anti-cancer agents would be useful based on the particular characteristics of the drugs and the cancer involved. The compounds of Formula (I) may also be useful when co-administered with radiation therapy. The compounds of Formula (I) can be present in the same dosage unit as the other therapeutic, chemotherapeutic, and anti-cancer agents. The compounds of Formula (I) and the other therapeutic, chemotherapeutic, and anti-cancer agents can also be present in separate dosage units.

It will be clear to a person skilled in the art that, where appropriate, the other therapeutic ingredient(s) may be used in the form of salts, for example as alkali metal or amine salts or as acid addition salts, or prodrugs, or as esters, for example lower alkyl esters, or as solvates, for example hydrates, to optimize the activity and/or stability and/or physical characteristics, such as solubility, of the therapeutic ingredient. It will be clear also that, where appropriate, the other therapeutic ingredients may be used in optically pure form.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical composition and thus, pharmaceutical compositions comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention. These combinations are of particular interest in respiratory diseases and are conveniently adapted for inhaled or intranasal delivery.

The individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical compositions. Preferably, the individual compounds will be administered simultaneously in a combined pharmaceutical composition. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.

Accordingly, the pharmaceutical compositions of the present invention include those that also comprise at least one additional therapeutically active agent, in addition to the compound of Formula (I).

The invention further includes a compound of Formula (I) in combination with one or more other drug(s).

Methods of Preparing the Compounds of Formula (I)

The compounds of this invention may be made by a variety of methods, including standard chemistry in light of the present disclosure. Illustrative general synthetic methods are set out below and then specific compounds of the Formula (I) are prepared in the Examples.

Compounds of Formula (I) may be prepared in light of the present disclosure via techniques known in the art of organic synthesis, examples of which are set forth in the following synthesis schemes. It would be well understood by those skilled in the art in light of the present disclosure that in all of the schemes described below, protecting groups for sensitive or reactive groups should be employed where necessary in accordance with general principles of chemistry. Protecting groups can be manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons). These groups can be removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. In certain other embodiments, a functional group presented in these schemes below can be converted to another functional group using standard functional group manipulation procedures known in the art. See, for example, “Comprehensive Organic Synthesis” (B. M. Trost & I. Fleming, eds., 1991-1992).

The selection of protecting groups as well as the reaction conditions and order of reaction steps shall be consistent with the preparation of compounds of Formula (I). Those skilled in the art will recognize in light of the present disclosure whether a stereocenter exists in compounds of Formula (I). When a compound is desired as a single enantiomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

The following solvents, reagents, protecting groups, moieties, and other designations may be referred to by their abbreviations:

Me=methyl; Et=ethyl; Pr=propyl; i-Pr=isopropyl, Bu=butyl; tert-Bu=tert-butyl; Ph=phenyl, and Ac=acetyl

μL=microliters

AcOH or HOAc=acetic acid

APCI=atmospheric-pressure chemical ionization

aq=aqueous

Bn=benzyl

Boc or BOC=tert-butoxycarbonyl

Bz=benzoyl

Cbz=benzyloxycarbonyl

DAST=diethylaminosulfur trifluoride

DBU=1,8-diazabicyclo[5.4.0]undec-7-ene

DCM=dichloromethane

DDQ=2,3-Dichloro-5,6-dicyano-1,4-benzoquinone

DEA=diethylamine

DMAP=4-Dimethylaminopyridine

DIBAL=diisobutylaluminum hydride

DIAD=diisopropyl azodicarboxylate

DIEA or Hünig's Base=N,N-diisopropylethylamine

DMF=dimethylformamide

DMSO=dimethyl sulfoxide

EA=ethyl acetate

EDC=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

EDTA=ethylenediamine tetraacetic acid

ESI=electrospray ionization

EtOAc=ethyl acetate

g=grams

h=hour

HMDS=1,1,1,3,3,3-hexamethyldisilazane

Hex=hexanes

HPLC=high-performance liquid chromatography

LDA=lithium diisopropylamide

LCMS=liquid chromatography mass spectrometry

LRMS=low resolution mass spectroscopy

min=minute

mg=milligrams

mL=milliliters

mmol=millimoles

MeOH=methanol

MPLC=medium pressure liquid chromatography

MTBE=methyl tert-butyl ether

MS=mass spectrometry

NBS=N-bromosuccinimide

NMO=4-methylmorpholine N-oxide

NMR=nuclear magnetic resonance spectroscopy

PE=petroleum ether

rac=racemic mixture

rt=room temperature (ambient, about 25° C.)

sat=saturated

SFC=supercritical fluid chromatography

TBSCl=t-butyldimethylsilyl chloride

TBS=t-butyldimethyl silyl

TEA=triethylamine (Et₃N)

TFA=trifluoroacetic acid

THF=tetrahydrofuran

TLC=thin layer chromatography

TMS=trimethylsilyl

TPAP=tetrapropylammonium perruthenate

TsOH=p-toluenesulfonic acid

General Methods

Methods for preparing compounds described herein are illustrated in the following synthetic schemes. The schemes are given for the purpose of illustrating the invention, but not for limiting the scope or spirit of the invention. Starting materials shown in the schemes can be obtained from commercial sources or be prepared based on procedures described in the literature.

The synthetic route illustrated in Scheme 1 is a general method for preparing various carbamates. Reaction of a starting amine A with a carbamoylating agent of structure B where X is a leaving group which includes halides, electron deficient phenols, imidazole, triazoles, or other moieties well-known to those trained in the art affords the target carbamate C.

The reaction procedures in Scheme 1 are contemplated to be amenable to preparing a wide variety of carbamoyl-substituted tetrahydroquinolines, carbamoyl-substituted benzoxazines, carbamoyl substituted tetrahydronaphthyridines, carbamoyl-substituted tetrahydropyridooxazines compounds having different substituents at the R¹, R², R^(a1), R^(b), R⁴, and Cy positions. A wide variety of alcohol starting materials necessary to prepare the carbamoylating reagent B are commercially available or readily prepared via known methods. Furthermore, if a functional group that is part of the R¹, R², R^(a1), R^(b), R⁴, or Cy group would not be amenable to a reaction condition described in Scheme 1, it is contemplated that the functional group can first be protected using standard protecting group chemistry and strategies, and then the protecting group is removed after completing the desired synthetic transformation.

Scheme 2 illustrates a different general method for preparing carbamates. Treatment of the amine A with phosgene, triphosgene, or other reagents known to convert aromatic or heteroaromatic amines to isocyanates, affords the isocyanate B which when treated with an alcohol C either without or with a catalyst (a base which includes but is not limited to triethyl amine, DBU, Hunig's base, or a metal catalyst such as a dibutyl tin dilaurate and numerous others known to those trained in the art) affords the carbamate D.

Scheme 3 illustrates a different general method for preparing carbamates. Treatment of the carboxylic acid A with conditions suitable to prepare an acyl azide (diphenyl phosphoryl azide, or isobutyl chloroformate and sodium azide, or other similar conditions known to those trained in the art) afford the acyl azide, which upon heating rearranges to form the isocyanate B. Treatment of the isocyanate with an alcohol C affords the carbamate D.

Scheme 4 illustrates another general method for preparing carbamates of the invention. Treatment of a halide or triflate (X=OTf) A under Pd-mediated coupling conditions with an unsubstituted carbamate C affords the carbamate D. The unsubstituted carbamate C can be prepared from alcohols B via treatment with either potassium isocyanate and acid or with sulfurisocyanatidic chloride.

Scheme 5 illustrates a general method for preparing alcohols and carbamoylating reagents suitable for the Scheme 1 and other general schemes below. Treatment of a ketone or aldehyde A with a Grignard reagent, R^(fs)Li, a R^(fs) metal, or a trialkylsilyl reagent (i.e., trimethyl silyl trifluoromethane) affords the alcohol B, which can be reacted with p-nitrochloroformate, carbonyldiimide, or phosgene to afford the carbamoylating reagents.

The synthetic route in Scheme 6 is a general method for preparing various carbamoyl-substituted benzoxazines and aza-benzoxazines compounds having a variety of protected aminomethyl side-chains, such as carbamates, ureas, sulfamides etc. Reaction of nitro-aryl aniline A with an epoxide provides benzoxazine B. The nitro group in benzoxazine B can be reduced in the presence of Boc₂O to a Boc carbamate group to provide Boc benzoxazine C. Mitsunobu reaction of benzoxazine C, followed by hydrolysis of the phthalamide provides aminomethyl benzoxazine E. Functionalization of the aminomethyl group and sulfonylation of the benzoxazine leads to Boc-carbamate G. Removal of the Boc carbamate group under acidic conditions and subsequent installation of the desired benzoxazine carbamate affords H.

Scheme 7 shows the synthesis of 3-substituted benzoxazines and aza-benzoxazines (or pyrido oxazines). Condensation of amino phenol A with chloro ketone B leads to imine C, which upon exhaustive reduction with NaBH₄ affords methyl alcohol D. Bis-sulfonylation, followed by S_(N)2 displacement of the activated methyl alcohol moiety with NaN₃ gives azide F. Lastly, reduction of the azide, functionalization of the corresponding aminomethyl side-chain group, and replacing of the Boc-carbamate with a suitable carbamate yields 3-substituted benzoxazine carbamate H.

An alternative method for preparing substituted benzoxazines and aza-benzoxazines stereoselectively [shown as (R,R,S), but not limited to] can be seen in Scheme 8. Addition of an enolate of the oxazolidinone A to the Boc-protected aldehyde B can afford a variety of (S,S,R) betahydroxycarboxylic acids C diastereoselectively (see J. Am. Chem. Soc. (2003) 125, 8218-8227). Protection of the alcohol moiety with a silyl group followed by a Curtius rearrangement in the presence of benzyl alcohol can afford the bis-carbamate D. This alcohol is added in via an SnAr displacement of the p-nitrophenyl halide of compound E, to afford the phenolic ether F. Exchange of the Boc-moiety with an SO₂Cy moiety affords the sulfonamide G, which via a palladium-mediated intramolecular cyclization can afford the benzoxazine H. This can be converted to the aniline I, and carbamoylated as described in the above schemes to afford the bis-carbamate J. Exchange of the benzoyl carbamate moiety with an appropriate amine protecting group (R) affords the final compounds K. The other diastereomers can also be prepared using the same route, but starting with the other enantiomers of compound A and/or B.

The synthetic route illustrated in Scheme 9 is a general method for preparing various carbamoyl-substituted tetrahydroquinoline and tetrahydronaphthyridine compounds. Nitration of A by reacting it with a mixture of nitric acid and sulfuric acid provides 7-nitro-tetrahydroquinoline or tetrahydronaphthyridine B. A sulfonamide group can be installed by reacting B with a mild base or sodium hydride and a sulfonyl chloride (Cy-SO₂Cl) to provide sulfonamide C. The nitro group in compound C can be reduced to an amino group providing aniline D, which can be reacted with a carbamoylating reagent from general Scheme 5 to provide the final carbamate E.

Scheme 10 illustrates a general method for preparing dihydroquinolines. Condensation of phenylene diamine A with ethyl acetoacetate under reflux (e.g., using Conrad-Limpach conditions) provides 7-amino-4-methylquinolin-2(1H)-one B. See, for example, Med. Chem Res. (2010) vol. 19, pages 193-209 for additional description of synthetic procedures known to those trained in the art. The amino group on quinolinone B can be reacted with a carbamoylating reagent from Scheme 5 to afford carbamate C. Reaction of carbamate C with mild base and a sulfonyl chloride (Cy-SO₂Cl) provides dihydroquinoline D.

Scheme 11 illustrates a general method for preparing fluoro-substituted, hydroxyl-substituted, and alkoxy-substituted tetrahydroquinoline and tetrahydronaphthyridine compounds. Oxidation of A using potassium permanganate provides ketone B. Ketone B can be reduced to alcohol C, reacted with a fluorinating agent (such as DAST) to provide difluorotetrahydroquinoline or tetrahydronaphthyridine D, or further oxidized to enone E. The oxidative conversion of ketone B to E can be carried using, for example, manganese dioxide, DDQ or selenium dioxide. Reaction of E with a fluorinating agent (such as DAST) provides fluoro-dihydroquinoline or tetrahydronaphthyridine F. Finally, as depicted below alkoxy-substituted tetrahydroquinoline or tetrahydronaphthyridine G can be prepared by reaction of alcohol C with methanesulfonyl chloride to provide an intermediate mesylate that is reacted with an alkoxide, such as sodium methoxide, to provide G.

Scheme 12 illustrates a general method for preparing tetrahydroquinolines and tetrahydronaphthyridines having an alkyl substituent attached to the 4-position of the bicyclic core. Amide coupling of halo-aniline A with an acid chloride or with an carboxylic acid with a coupling reagent provides amide B. Synthetic intermediate B is subjected to Heck Coupling conditions to provide C, which can be reduced to lactam D. Synthetic intermediate D can be converted to the carbamate E, and subsequent reaction with the desired sulfonyl chloride, followed by reduction of the lactam moiety, provides the desired tetrahydroquinoline or tetrahydronaphthyridine G.

The reaction procedures in Scheme 13 are contemplated to be amenable to preparing a wide variety of carbamoyl-substituted tetrahydro-1,5-naphthyridine compounds having different substituents at the R¹ and R³ positions. For example, numerous substituted 5-bromo-3-aminopyridines are known in the literature and/or are commercially available, such as 5-bromo-6-methyl-pyridin-3-amine, 5-bromo-4-methyl-pyridin-3-amine, 5-amino-3-bromo-2-methoxylpyridine, and 5-bromo-4,6-dimethyl-pyridin-3-amine. Furthermore, if a functional group that is part of R¹ or R³ would not be amenable to a reaction condition described in Scheme 15, it is contemplated that the functional group can first be protected using standard protecting group chemistry and strategies, and then the protecting group is removed after completing the desired synthetic transformation. See, for example, Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2^(nd) ed.; Wiley: New York, 1991, for further description of protecting chemistry and strategies known to those trained in the art. In certain other embodiments, a functional group in substituent R¹ and R³ in tetrahydro-1,5-naphthyridine F can be converted to another functional group using standard functional group manipulation procedures known in the art. See, for example, “Comprehensive Organic Synthesis” (B. M. Trost & I. Fleming, eds., 1991-1992).

Scheme 14 illustrates an alternative general method for preparing substituted 5,6,7,8-tetrahydro-1,5-naphthyridine compounds. Reduction of halo-nitro-pyridine A with dissolving metals provides halo-amino-pyridine B. Exemplary dissolving metal reduction conditions include the use of, for example, (1) SnCl₂ in HCl as described by Adams et al. in WO 2008/150827, or (2) Fe in HCl or NH₄Cl as described by Carroll et al. in J. Med. Chem. 2002, 45, 4755-4761 and Oalmann et al. in WO 2010/071853. Reaction of halo-amino-pyridine B with a sulphonyl chloride or sulfamoyl chloride provides halo-pyridinyl sulfonamide C. Reaction of halo-pyridinyl sulfonamide C with a vinyl boronic acid or vinyl stannane provides alkene D, which can be allylated using, for example, an allyl halide under basic conditions or an allyl alcohol under Mitsunobu conditions to provide di-alkene E. Di-alkene E can be subjected to ring closing metathesis conditions to provide dihydro-1,5-naphthyridine F. For exemplary ring closing metathesis conditions, see, for example, Mitsuhiro et al. in J. Org. Chem. 2006, 71, 4255-4261. Reduction of dihydro-1,5-naphthyridine F provides saturated tetrahydro-1,5-naphthyridine G. The methyl ester on tetrahydro-1,5-naphthyridine G can be converted to a carboxylic acid under hydrolytic conditions, and the resulting carboxylic acid is subjected to reaction conditions that facilitate Curtius rearrangement (see, for example, Ninomiya in Tetrahedron 1974, 30, 2151-2157) to provide intermediate or final tetrahydronaphthyridinyl carbamate H. The carbamate functional group of an intermediate tetrahydronaphthyridinyl carbamate H can be converted to an amino group using standard carbamate protecting group removal procedures, and the resulting amino-tetrahydronaphthyridine can be reacted with carbamoylating reagents to provide carbamoyl-tetrahydro-1,5-naphthyridine I.

Scheme 15 illustrates a general route to providing oxygenated 5,6,7,8-tetrahydro-1,5-naphthyridine compounds. Chiral osmylation of alkene A provides diol B. For exemplary chiral osmylation procedures, see, for example, Noe et al. in Org. Reactions 2005, 66, 109. Reduction of diol B provides alcohol C. The hydroxyl group in compound C can be alkylated to provide ether D, or the hydroxyl group can be converted to other functional groups using functional group conversion procedures known in the art.

Scheme 16 illustrates another general procedure for preparing 5,6,7,8-tetrahydro-1,5-naphthyridine compounds. Treatment of halo-nitro-pyridine A with a Negishi reagent under Pd-mediated conditions provides diester B. For additional description of related procedures, see, for example, Zhu et al. in J. Org. Chem. 1991, 56, 1445-1453. Dissolving metal reduction of diester B with in situ cyclization affords dihydro-1,5-naphthyridin-2(1H)-one C. Reaction of dihydro-1,5-naphthyridin-2(1H)-one C with a protecting group installation reagent (e.g., benzylbromide (Bn-Br)) provides protected amide D, which after hydrolysis and in situ formation of the azide and Curtius rearrangement provides carbamate E. A substituent can be installed alpha to the amide group by reaction of carbamate E with base and an electrophile (e.g., R³-halide) to provide substituted-dihydro-1,5-naphthyridin-2(1H)-one F. Reduction of substituted-dihydro-1,5-naphthyridin-2(1H)-one F can be performed by reaction with a hydride (e.g., a borane or lithium aluminum hydride) to provide tetrahydro-1,5-naphthyridine G. Next, protecting groups (e.g., the benzyl and carbamate protecting group) are removed and the resulting amine is reacted with carbamoylating reagents from Scheme 5 to provide carbamoyl-tetrahydro-1,5-naphthyridine I and reacted with a sulphonyl chloride to provide the final tetrahydro-1,5-naphthyridine J.

Scheme 17 illustrates another procedure for preparing substituted tetrahydro-1,5-naphthyridines. Reacting halo-nitro-pyridine A with a Negishi reagent (formed from a 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate) provides amino acid B. Then, amino acid B is subjected to dissolving metal reduction conditions with in situ cyclization to provide dihydro-1,5-naphthyridin-2(1H)-one C. Subjecting dihydro-1,5-naphthyridin-2(1H)-one C to hydrolysis conditions provides a carboxylic acid (not shown), that after in situ formation of an acyl azide followed by a Curtius rearrangement provides bis-carbamate D. Selective reduction of the amide group in bis-carbamate D using borane or lithium aluminum hydride provides tetrahydro-1,5-naphthyridine E. Reaction of tetrahydro-1,5-naphthyridine E with a sulphonyl chloride or sulfamoyl chloride provides sulfonamide F. Next, the benzylcarbamate protecting group is removed from sulfonamide F to provide an amino-tetrahydro-1,5-naphthyridine (not shown) that can be subjected to carbamoylating reagents from Scheme 5 to provide carbamoyl-tetrahydro-1,5-naphthyridine G. The remaining Boc protecting group on carbamate-tetrahydro-1,5-naphthyridine G can be removed by treatment with acid to provide amino-tetrahydro-1,5-naphthyridine H. It would be understood by those trained in the art that the amino group on amino-tetrahydro-1,5-naphthyridine H can be converted to other functional groups (e.g., by reaction with an alkylating agent(s), aldehyde (reductive alkylations), acyl halide, sulphonyl chloride, isocyanate, and the like) to afford the compound I.

Scheme 18 illustrates another general method for preparing substituted tetrahydro-1,5-naphthyridines. Carbamoylation of amino-pyridine A provides pyridine B, which is treated with an allylic alcohol under Heck conditions to provide compound C. For an exemplary description of such Heck reaction conditions, see, for example, Colbon et al. in J. Org. Letters 2011, 13, 5456-5459. Subjecting Compound C to reductive cyclization conditions followed by treatment with a sulphonyl chloride provides sulfonamide-tetrahydro-1,5-naphthyridine D.

Scheme 19 illustrates a general method for preparing 2-substituted-2,3-dihydro-1H-pyrido[2,3-b]oxazines. Reaction of chloro-pyridine A with hydroxy-ketone B provides nitro-pyridyl ether C. Exhaustive reduction (e.g., using Raney Nickel) of compound C provides amino-dihydro-1H-pyrido[2,3-b]oxazine D. Carbamoylation of pyrido[2,3-b]oxazine D provides pyrido[2,3-b]oxazine E, which is treated with a sulphonyl chloride to afford final compound F.

Scheme 20 illustrates a general method for preparing substituted-2,3-dihydro-1H-pyrido[2,3-b]oxazines. Reacting chloro-pyridine A with protected hydroxyketone (or a protected hydroxyaldehyde) B provides an aryl-alkyl ether intermediate (not shown) that upon acid hydrolysis provides dinitropyridyl-ketone (or dinitropyridyl-aldehyde) C. Exhaustive reduction (e.g., using Raney Nickel) of compound C provides amino-dihydro-1H-pyrido[2,3-b]oxazine D. Carbamoylation of the amino group in compound D affords dihydro-1H-pyrido[2,3-b]oxazine E, which is treated with a sulphonyl chloride or a sulfamoyl chloride to afford the final compound F.

In embodiments where it is desirable to prepare pyrido-oxazines F in chiral form, a protected chiral hydroxyketone B can be used as starting material.

Scheme 21 illustrates another general method for preparing substituted-2,3-dihydro-1H-pyrido[2,3-b]oxazines. Reaction of halo-pyridine A with a 2-hydroxyester provides nitro-carboxypyridine B. Subjecting nitro-carboxypyridine B to dissolving metal reduction conditions with in situ cyclization affords 1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one C. Subjecting 1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one C to hydrolysis conditions provides a carboxylic acid (not shown), that after in situ formation of an acyl azide followed by a Curtius rearrangement provides carbamate D. Selective reduction of the amide group in carbamate D using borane or lithium aluminum hydride provides dihydro-1H-pyrido[2,3-b]oxazine E. Reaction of dihydro-1H-pyrido[2,3-b]oxazine E with a sulphonyl chloride provides sulfonamide F. Next, the carbamate protecting group is removed from sulfonamide F to provide amino-dihydro-1H-pyrido[2,3-b]oxazine G that can be carbamoylated as described in Scheme 5 to provide dihydro-1H-pyrido[2,3-b]oxazine H.

Scheme 23 illustrates an alternate general method for preparing substituted-2,3-dihydro-1H-pyrido[2,3-b]oxazines. Reaction of halo-nitropyridine A with a hydroxyalkyl-epoxide provides nitro-pyridyl ether B. Subjecting nitro-pyridyl ether B to dissolving metal reduction conditions with in situ cyclization affords a bicyclic alkoxide intermediate (not shown) that is reacted with an alcohol protecting group reagent (e.g., a trialkylsilylchloride or with an alkyl halide if the final target is an ether) to provide bicyclic ether C. Reaction of bicyclic ether C with a sulphonyl chloride or sulfamoyl chloride provides sulfonamide-pyrido-oxazine D. The methyl ester on sulfonamide-pyrido-oxazine D can be converted to a carboxylic acid using hydrolytic conditions to provide an intermediate carboxylic acid compound (not shown), that is converted to an acyl azide followed by a Curtius rearrangement to provide carbamate E. The carbamate protecting group may be removed using standard deprotection conditions to provide a bicyclic amine (not shown) that can be carbamoylated to form 5,6,7,8-tetrahydro-1,5-naphthyridine F. In embodiments, where R^(IX) is a protecting group (e.g., a trialkylsilyl group), R^(IX) may be removed using standard deprotection conditions (e.g., using tetra-n-butylammonium fluoride) to provide alcohol G.

Scheme 24 shows the general synthetic route to tetrahydroquinoline carboxylic acids and acid derivatives as analogues of the benzoxazine core. Halogenation of readily available quinoline B and subsequent Heck reaction affords alpha,beta-unsubstituted ester C. Partial reduction of the quinoline moiety, in addition to reduction of the nitro and double bond groups in the presence of Boc₂O, affords Boc-carbamate D. Compound D can subsequently be elaborated to the desired tetrahydroquinoline carboxylic acid derivative H using similar chemistry as described above.

EXAMPLES

The invention now being generally described will be more readily understood by reference to the following examples, which are included for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention. Starting materials useful for preparing the compounds of Formula (I) can be obtained from commercial sources or are readily prepared from commercially available materials using transformations which are known to those of skill in the art of organic chemistry.

Example 1 Synthesis of (R)-tert-butyl (2-(hydroxymethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (1)

The title compound was prepared according to the procedures described below.

Part I—Synthesis of 2-[[(2S)-3-chloro-2-hydroxypropyl]amino]-4-nitrophenol

A solution of 2-amino-4-nitrophenol (250.0 g, 1.62 mol) and (2S)-2-(chloromethyl)oxirane (330.0 g, 3.57 mol) in ethanol:water (2500 mL:25 mL) was stirred for twelve hours at 60° C. in an oil bath. The resulting mixture was cooled and concentrated to afford 2-[[(2S)-3-chloro-2-hydroxypropyl]amino]-4-nitrophenol as a brown oil.

Part II—Synthesis of [(2R)-6-nitro-3,4-dihydro-2H-1,4-benzoxazin-2-yl]methanol

A solution of 2-[[(2S)-3-chloro-2-hydroxypropyl]amino]-4-nitrophenol (400 g, 1.62 mol) in ethanol (2.5 L) and potassium carbonate (134.5 g, 973 mmol) was stirred for twelve hours at 90° C. in an oil bath. The mixture was filtered and the filtrate was concentrated. The residue was diluted with water (1.5 L) and extracted three times with ethyl acetate (1 L). The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated. The residue was purified via MPLC over silica gel eluting with ethyl acetate/petroleum ether (1:1) to afford [(2R)-6-nitro-3,4-dihydro-2H-1,4-benzoxazin-2-yl]methanol as a red solid.

Part III—Synthesis of ((R)-2-hydroxymethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-carbamic acid tert-butyl ester

The atmosphere above a solution of [(2R)-6-nitro-3,4-dihydro-2H-1,4-benzoxazin-2-yl]methanol (137 g, 652 mmol), palladium on carbon (13.7 g) and di-tert-butyl dicarbonate (157 g, 717 mmol) in methanol (1400 mL) was exchanged with hydrogen. The resulting solution was stirred for twelve hours at room temperature. The mixture was filtered, and the filtrate was concentrated. The crude product was purified by re-crystallization from ether to afford ((R)-2-hydroxymethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-carbamic acid tert-butyl ester as an off-white solid. LRMS (ESI) calculated for C₁₄H₂₀N₂O₄ 280. Found: 225 (M-C₄H₈+H)⁺; 281 (M+H)⁺. ¹H NMR (300 MHz, CDCl₃): δ 6.92 (s, 1H), 6.71 (d, J=8.7 Hz, 1H), 6.41 (dd, J=8.7, 2.4 Hz, 1H), 6.26 (s, 1H), 4.20-4.21 (m, 1H), 3.76-3.86 (m, 2H), 3.26-3.35 (m, 2H), 1.53 (s, 9H).

Part IV—Synthesis of (R)-tert-butyl (2-(hydroxymethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a stirred solution of (R)-tert-butyl (2-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (2.0 g, 7.1 mmol) in pyridine (14 mL) and anhydrous THF (7 mL) was added dropwise 3-(trifluoromethyl) benzene-1-sulfonyl chloride (2.6 g, 10.6 mmol) at room temperature. After an hour, the resulting mixture was concentrated and the residue was partitioned between ethyl acetate (30 mL) and water (30 mL). The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried (MgSO₄) and concentrated. The residue was purified by column chromatography on silica gel eluting with petroleum ether:ethyl acetate (5:1) to give (R)-tert-butyl (2-(hydroxymethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 1.52 (s, 10H) 1.88 (t, J=6.4 Hz, 1H) 3.39-3.46 (m, 1H) 3.57 (dd, J=9.2, 2.4 Hz, 1H) 3.65-3.81 (m, 2H) 4.29 (dd, J=14.0, 2.0 Hz, 1H) 6.44 (br s, 1H) 6.78 (d, J=9.2 Hz, 1H) 7.17 (d, J=7.6 Hz, 1H) 7.59-7.68 (m, 1H) 7.76 (d, J=2.0 Hz, 1H) 7.84 (d, J=8.0 Hz, 1H) 7.90 (d, J=8.0 Hz, 1H) 8.05 (s, 1H). LRMS (ESI) calculated for C₂₁H₂₄F₃N₂O₆S (M+H)⁺: 489. Found: 489.

Example 2 Preparation of additional (R)-tert-butyl (2-(hydroxymethyl)-4-(optionally substituted aryl or heteroaryl-sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamates

The compounds in Table 1 below were prepared based on the experimental procedures described in Example 1 and elsewhere in the detailed description, and can be achieved by one of skill in the art in light of the present disclosure. Starting materials can be obtained from commercial sources or readily prepared from commercially available materials.

TABLE 1 Ex. No. Structure Name Observed m/z 2A

(R)-tert-butyl (4-((5-bromo-2- chloropyridin-3-yl)sulfonyl-2- (hydroxymethyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 556   (M + Na)⁺ 2B

(R)-4-((6-((tert- butoxycarbonyl)amino)-2- (hydroxymethyl)-2H- benzo[b][1,4]oxazin-4(3H)- yl)sulfonyl)-1-(difluoromethyl)-3- methyl-1H-pyrazol-2-e 419.2 (M-tBu + H)⁺ 2C

[(R)-4-(3-chloro-benzenesulfonyl)-2- hydroxymethyl-3,4-dihydro-2H- benzo[1,4]oxazin-6-yl]-carbamic acid tert-butyl ester 399.0 (M-tBu + H)⁺ 2D

(R)-tert-butyl (4-((5-bromopyridin-3- yl)sulfonyl)-2-(hydroxymethyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 500   (M + H)⁺ 2E

(R)-tert-butyl (2-(hydroxymethyl)-4- ((1-methyl-1H-pyrazol-4- yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 369   (M-tBu + H)⁺ 2F

(R)-tert-butyl (2-(hydroxymethyl)-4- ((3-(methylsulfonyl)phenyl)sulfonyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin- 6-yl)carbamate 443.0 (M-tBu + H)⁺ 2G

(R)-tert-butyl (4-((2-chloro-5- methylpyridin-3-yl)sulfonyl)-2- (hydroxymethyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 470   (M + H)⁺ 2H

(R)-tert-butyl (4-((3- cyanophenyl)sulfonyl)-2- (hydroxymethyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 390.0 (M-tBu + H)⁺

Example 3 Synthesis of (R)-tert-butyl (2-(hydroxymethyl)-4-((5-methyl-2-oxo-1,2-dihydropyridin-3-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (3)

A solution of (R)-tert-butyl (4-((2-chloro-5-methylpyridin-3-yl)sulfonyl)-2-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (102 mg, 0.217 mmol), and chloro[2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II) (22.36 mg, 0.033 mmol) in p-dioxane (1085 μL) and water (1085 μl) was purged thoroughly with argon. Potassium hydroxide (48.7 mg, 0.868 mmol) was then added and the reaction was sealed and heated at 80° C. for two hours. The mixture was cooled, diluted with ethyl acetate, washed twice with aqueous sodium hydrogen carbonate and then with brine. The aqueous layers were back extracted once with ethyl acetate. The combined organic layers were dried (Na₂SO₄) and concentrated. The residue was purified by MPLC eluting with a gradient of 1-10% methanol in dichloromethane to afford (R)-tert-butyl (2-(hydroxymethyl)-4-((5-methyl-2-oxo-1,2-dihydropyridin-3-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate as a yellow solid. ¹H NMR (600 MHz, DMSO-d6) δ 12.17 (s, 1H), 9.11 (s, 1H), 8.19 (d, J=2.2 Hz, 1H), 7.74 (s, 1H), 7.52 (s, 1H), 6.76 (dd, J=1.9, 8.8 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 5.01 (t, J=5.6 Hz, 1H), 4.38 (dd, J=1.8, 13.5 Hz, 1H), 4.08-4.02 (m, 1H), 3.64-3.56 (m, 1H), 3.57-3.51 (m, 1H), 3.44 (dd, J=9.1, 13.3 Hz, 1H), 2.09 (s, 3H), 1.42 (s, 9H). LRMS (ESI) calculated for C₂₀H₂₅N₃O₇S (M+H)⁺: 452. Found: 452.

Example 4 Synthesis of (R)-tert-butyl (4-((4-fluorophenyl)sulfonyl)-2-(2-hydroxypropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate and (S)-tert-butyl (4-((4-fluorophenyl)sulfonyl)-2-(2-hydroxypropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Example Nos. 4A and 4B)

The title compound was prepared according to the procedures described below.

Part I—Synthesis of ethyl 4-((4-fluorophenyl)sulfonyl)-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate

A mixture of ethyl 6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (4.5 g, 17.9 mmol), 4-fluorobenzene-1-sulfonyl chloride (4.52 g, 23.3 mmol) and pyridine (7.07 g, 89.5 mmol) in THF (100 mL) was stirred at 60° C. for fifteen hours. The reaction mixture was concentrated, and the residue was partitioned between dichloromethane (100 mL) and water (100 mL). The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated. The residue was purified by column chromatography on silica gel eluting with petroleum ether:ethyl acetate (5:1) to afford ethyl 4-((4-fluorophenyl)sulfonyl)-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate as a yellow solid. LRMS (ESI) calculated for C₁₇H₁₆FN₂O₇S (M+H)⁺: 411. Found: 411.

Part II—Synthesis of ethyl 6-((tert-butoxycarbonyl)amino)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate

To a solution of ethyl 4-((4-fluorophenyl)sulfonyl)-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (5.0 g, 12.2 mmol) and di-tert-butyl dicarbonate (2.92 g, 13.4 mmol) in ethanol (100 mL) was added Pd/C (1.0 g, 10% wt) under argon. The suspension was degassed under vacuo and purged with hydrogen three times. The mixture was stirred under the pressure of 40 psi hydrogen at 30° C. for four hours. The suspension was filtered through a pad of CELITE and the filter cake was washed with ethanol (20 mL). The combined filtrates were concentrated to dryness to give ethyl 6-((tert-butoxycarbonyl)amino)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate as a yellow solid. LRMS (ESI) calculated for C₂₂H₂₆FN₂O₇S (M+H)⁺: 481. Found: 481.

Part III—Synthesis of (R)-tert-butyl (4-((4-fluorophenyl)sulfonyl)-2-(2-hydroxypropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate and (S)-tert-butyl (4-((4-fluorophenyl) sulfonyl)-2-(2-hydroxypropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a stirred solution of ethyl 6-((tert-butoxycarbonyl)amino)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (5.5 g, 11.5 mmol) in anhydrous THF (70 mL) was added a 3M solution of methyl magnesium bromide (38.3 mL, 115 mmol) in ethyl ether at −78° C., and the resultant mixture was warmed to 25° C. and stirred for an additional hour. The reaction mixture was poured into saturated ammonium chloride (500 mL), and extracted twice with dichloromethane (500 mL each). The combined organic layers were dried (Na₂SO₄), and concentrated. The residue was purified by column chromatography on silica gel eluting with petroleum ether:ethyl acetate (3:1) to afford a racemic mixture of the title compounds as a white solid, which was chirally separated by SFC (Instrument: Thar SFC 350; Column: AD 300 mm*50 mm, 10 um; Mobile phase: A: Supercritical CO₂, B: MeOH (0.1% NH₃.H₂O), A: B=65:35 at 240 mL/min; Column Temp: 38° C.; Nozzle Pressure: 100 Bar; Nozzle Temp: 60° C.; Evaporator Temp: 20° C.; Trimmer Temp: 25° C.; Wavelength: 220 nm) to afford the two isomers.

Isomer 1: (R)-tert-butyl (4-((4-fluorophenyl)sulfonyl)-2-(2-hydroxypropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate ¹H NMR (400 MHz, CDCl₃) δ 7.62-7.75 (m, 3H), 7.32 (br. s., 1H), 7.15 (t, J=8.4 Hz, 2H), 6.81 (d, J=9.2 Hz, 1H), 6.44 (br. s., 1H), 4.38 (dd, J=2.0, 14.4 Hz, 1H), 3.19 (dd, J=10.4, 14.4 Hz, 1H), 3.03 (dd, J=1.6, 10.4 Hz, 1H), 1.53 (s, 9H), 1.20 (d, J=12.4 Hz, 6H). LRMS (ESI) calculated for C₂₂H₂₈FN₂O₆S (M+H)⁺: 467. Found: 467.

Isomer 2: (S)-tert-butyl (4-((4-fluorophenyl)sulfonyl)-2-(2-hydroxypropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate. ¹H NMR (400 MHz, CDCl₃) δ 7.65-7.74 (m, 3H), 7.33 (br. s, 1H), 7.15 (t, J=8.4 Hz, 2H), 6.81 (d, J=8.4 Hz, 1H), 6.44 (br. s, 1H), 4.38 (dd, J=2.0, 14.0 Hz, 1H), 3.19 (dd, J=10.4, 14.0 Hz, 1H), 3.03 (dd, J=1.6, 10.4 Hz, 1H), 1.53 (s, 9H), 1.20 (d, J=12.4 Hz, 6H). LRMS (ESI) calculated for C₂₂H₂₈FN₂O₆S (M+H)⁺: 467. Found: 467.

Example 5 Preparation of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl 4-(3,4-difluorophenylsulfonyl)-2-(2,2,2-trifluoroacetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylcarbamate (5)

Step 1-Preparation of 1-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2,2,2-trifluoroethanone

To a solution of (R)-4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic acid (7.5 g, 23.85 mmol) in dichloromethane (150 mL) and 2 drops of DMF at 0° C. was added oxalyl chloride (12 mL). The mixture was allowed to warm to room temperature and was stirred for an additional two hours. The mixture was concentrated. To a solution of the resulting residue in dichloromethane (150 mL) at 0° C. was added trifluoroacetic anhydride (19.5 mL, 143.1 mmol) followed by slow addition of pyridine (15 mL). The mixture was allowed to warm to room temperature and stirred for 24 hours. The mixture was cooled in an ice bath, ice water was added into the mixture slowly, and the mixture was stirred at room temperature for an additional hour. The mixture was extracted twice with dichloromethane. The combined organic phases were washed with 1 N HCl, brine, dried (Na₂SO₄) and concentrated. The residue was purified by column chromatography on silica gel eluting with petroleum ether:ethyl acetate (20:1 to 10:1) to give the title compound as a red oil. LCMS (ESI): calculated for C₁₇H₁₃F₃N₂O₄ (M+H)⁺: 367. found: (M+H₂O+H)⁺ 385.

Step 2—Preparation of 1-(6-amino-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2,2,2-trifluoroethanone

To a solution of 1-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2,2,2-trifluoroethanone (1.0 g, 2.73 mmol) in ethyl acetate (30 mL) purged with nitrogen was added Pd/C (1 g). The atmosphere above the solution was exchanged with a balloon of hydrogen and was stirred at room temperature for 16 hours. The mixture was filtered through a pad of CELITE and the filtrate was concentrated to afford the title compound as a dark-white solid which was used without any further purification. LCMS (ESI): calculated for C₁₀H₉F₃N₂O₂ (M+H)⁺: 247. found: 247.

Step 3-Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl 2-(2,2,2-trifluoroacetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylcarbamate

To a solution of 1-(6-amino-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2,2,2-trifluoroethanone (2.8 g, 23.6 mmol) and 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (2.78 g, 25.9 mmol) in DMSO (28 mL) was added concentrated HCl (1.2 mL, 13.44 mmol) and the mixture was stirred at 70° C. for 5 hours. The mixture was diluted with saturated NaHCO₃ and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated. The residue was purified via MPLC to afford an off-white solid (dichloromethane: ethyl acetate=20:1-10:1). LCMS (ESI): calculated for C₁₅H₁₄F₆N₂O₄ (M+H)⁺: 401. found (M+H₂O+H)⁺: 419.

Step 4—Preparation of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl 4-(3,4-difluorophenylsulfonyl)-2-(2,2,2-trifluoroacetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylcarbamate

To a room temperature solution of 1,1,1-trifluoro-2-methylpropan-2-yl 2-(2,2,2-trifluoroacetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylcarbamate (400 mg, 1.0 mmol) in THF (6 mL) and pyridine (2 mL) was added 3,4-difluorobenzene-1-sulfonyl chloride (425 mg, 2.0 mmol) and the mixture was stirred overnight. The mixture was diluted with 1 N of HCl (final mixture had a pH=3) and was extracted twice with ethyl acetate. The combined organic phase was washed with brine, dried (Na₂SO₄) and concentrated. The residue was purified by column chromatography on silica gel eluting with a gradient of petroleum ether:ethyl acetate of 10:1 to 3:1 to afford the title compound as a yellow oil. LCMS (ESI): calculated for C₂₁H₁₆F₈N₂O₆S (M+H)⁺: 577. found (M+H₂O+Na)⁺: 617; ¹H-NMR (400 MHz, CD₃OD) δ 7.92 (br s, 1H), 7.61-7.65 (m, 1H), 7.42-7.50 (m, 2H), 7.09-7.10 (m, 1H), 6.75-6.81 (m, 1H), 4.44-4.55 (m, 1H), 3.45-3.47 (m, 1H), 3.24-3.25 (m, 2H), 1.73 (s, 6H).

Example 6 Preparation of additional 1,1,1-trifluoro-2-methylpropan-2-yl benzoxazines

The compound in Table 2 below is prepared based on the experimental procedures described in Example 5, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 2 Ex. Observed No. Structure Name m/z 6A

(R and S)-1,1,1-trifluoro-2- methylpropan-2-yl (4-((3-chloro-1- ethyl-1H-pyrazol-4-yl)sulfonyl)-2- (2,2,2-trifluoroacetyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6- yl)carbamate 633 (M + H₂O + Na)⁺ 6B

(R and S)-1,1,1-trifluoro-2- methylpropan-2-yl (4-((4- fluorophenyl)sulfonyl)-2-(2,2,2- trifluoroacetyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 559 (M + H)+

Example 7 Synthesis of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (7)

The title compound was prepared according to the procedures described below.

Part I—Synthesis of (S)-tert-butyl (2-(((benzyloxy)carbonyl)aminomethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To (S)-tert-butyl (2-(aminomethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (2.5 g, 8.95 mmol), N,N′-diisopropylethylamine (3.91 mL, 22.4 mmol), and dichloromethane (44.7 mL) was added dropwise benzyl chloroformate (1.28 mL, 8.95 mmol) over five minutes at 0° C. The reaction was warmed to room temperature and stirred for four hours. The mixture was diluted in saturated sodium bicarbonate and extracted with isopropanol/chloroform (1:3 v/v). The combined organic layers were washed with brine, dried (MgSO₄) and concentrated to afford (S)-tert-butyl (2-(((benzyloxy)carbonyl)aminomethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate.

Part II—Synthesis of (S)-tert-butyl (2-(((benzyloxy)carbonyl)aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A mixture of (S)-tert-butyl (2-(((benzyloxy)carbonyl)aminomethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (7.4 g, 17.90 mmol), pyridine (89 mL), and 4-fluorobenzene-1-sulfonyl chloride (6.97 g, 35.8 mmol) was heated at 60° C. for two hours. The mixture was partitioned between isopropanol chloroform and saturated sodium bicarbonate. The organic layer was washed with brine, dried (MgSO₄) and concentrated to afford (S)-tert-butyl (2-(((benzyloxy)carbonyl)aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate.

Part III—Synthesis of (S)-benzyl ((6-amino-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)carbamate

A mixture of (S)-tert-butyl (2-(((benzyloxy)carbonyl)aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (10 g, 17.49 mmol) and 4M HCl in p-dioxane (109 mL, 437 mmol) was stirred at room temperature for 30 minutes and concentrated to afford (S)-benzyl ((6-amino-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)carbamate.

Part IV—Synthesis of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(((benzyloxy)carbonyl)aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-benzyl ((6-amino-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)carbamate (4.00 g, 7.87 mmol), dichloromethane (39.4 mL), and triethyl amine (6.59 mL, 47.2 mmol) was added 4-nitrophenyl (1,1,1-trifluoro-2-methylpropan-2-yl) carbonate (5.77 g, 19.69 mmol) and 4-N,N-dimethylaminopyridine (0.192 g, 1.575 mmol). The mixture was stirred at room temperature overnight and poured into saturated sodium bicarbonate. The mixture was extracted with isopropanol/chloroform. The combined organic layers were washed with 1N NaOH, dried (MgSO₄) and concentrated. The residue was purified via chromatography eluting with a gradient of (0-100% ethyl acetate/hexanes) to afford (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(((benzyloxy)carbonyl)aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate.

Part V—Synthesis of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A solution of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(((benzyloxy)carbonyl)aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (750 mg, 1.20 mmol) and methanol (12 mL) was purged with nitrogen. Palladium 10% on carbon (76 mg, 0.072 mmol) was added. The atmosphere was exchanged with hydrogen at one atmosphere and stirred for four hours. The mixture was filtered through CELITE. The filtrate was concentrated to afford (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate as a white solid. ¹H NMR: (300 MHz, CDCl₃): δ 9.81 (1H, s), 8.00 (2H, s), 7.92 (1H, s), 7.84 (2H, m), 7.46 (2H, m), 7.22 (1H, d, J=9.7 Hz), 6.80 (1H, d, J=8.24 Hz), 4.41 (1H, dd, J=11.79 Hz, 2.66 Hz), 3.72 (1H, m), 3.34 (1H, m), 3.20 (1H, m), 2.96 (1H, m), 1.70 (6H, s). LRMS (ESI) calculated for C₂₀H₂₁F₄N₃O₅S (M+H)⁺: 492. Found 492.1.

Example 8 Synthesis of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(((benzyloxy)carbonyl)aminomethyl)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (8)

To a mixture of (S)-benzyl ((6-amino-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)carbamate hydrochloride (4.80 g, 8.85 mmol), dichloromethane (88 mL), and triethyl amine (7.40 mL, 53.1 mmol) was added 4-nitrophenyl (1,1,1-trifluoro-2-methylpropan-2-yl) carbonate (5.71 g, 19.47 mmol). The mixture was stirred for one day at room temperature. The mixture was partitioned between isopropanol/chloroform (1:3, v/v) and saturated sodium bicarbonate. The organic layer was washed with 1N NaOH, dried (MgSO₄) and concentrated. The residue was purified by MPLC eluting with a gradient of 0-100% ethyl acetate/hexanes to afford (S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(((benzyloxy)carbonyl)aminomethyl)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate as a white solid. LRMS (ESI) calculated for C₂₈H₂₆ClF₄N₃O₇SNa (M+Na): ⁺ 682. Found: 682.2. ¹H NMR: (300 MHz, CDCl₃) δ 9.77 (1H, s), 7.98 (1H, m), 7.90 (1H, s), 7.70 (1H, m), 7.61 (1H, t, J=10.13 Hz), 7.53 (1H, t, J=6.51 Hz), 7.35 (3H, m), 7.31 (1H, m), 7.12 (1H, d, J=9.41 Hz), 6.77 (1H, d, J=7.95 Hz), 5.04 (2H, m), 4.31 (1H, m), 3.53 (1H, m), 3.26 (3H, m), 3.19 (1H, m), 1.70 (6H, m).

Example 9 Synthesis of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((4-fluorophenyl)sulfonyl)-2-((3-(tetrahydro-2H-pyran-4-yl)ureido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (9)

A solution of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (30 mg, 0.061 mmol), 4-isocyanatotetrahydro-2H-pyran (31.0 mg, 0.244 mmol), triethyl amine (34.0 μL, 0.244 mmol), and dichloromethane (610 μL) was stirred overnight. The mixture was partitioned between saturated sodium bicarbonate and dichloromethane. The organic layer was dried (MgSO₄) and concentrated. The residue was dissolved in DMSO (1.5 mL), filtered, and purified by reverse phase chromatography to afford (S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((4-fluorophenyl)sulfonyl)-2-((3-(tetrahydro-2H-pyran-4-yl)ureido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate. LRMS (ESI) calculated for C₂₆H₃₁F₄N₄O₇S (M+H): ⁺: 619. Found: 619. ¹H NMR: (300 MHz, CDCl3) δ 9.76 (1H, s), 7.90 (1H, s), 7.73 (2H, m), 7.38 (2H, t, J=8.58 Hz), 7.18 (1H, d, J=10.13 Hz), 6.76 (1H, d, J=9.36 Hz), 6.03 (1H, d, J=6.96 Hz), 5.97 (1H, m), 4.26 (1H, m), 3.78 (3H, m), 3.33 (5H, m), 3.14 (2H, m), 1.69 (7H, m), 1.30 (2H, m).

Example 10 Additional Ureas and Carbamates of Aminobenzoxazines

The urea and bis-carbamate compounds in Table 3 below were prepared based on the experimental procedures described in Examples 7, 8, and 9 and elsewhere in the detailed description, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 3 Ex. Observed No. Structure Name m/z 10A

(S)-tert-butyl (2- (((benzyloxy)carbonyl)aminomethyl)- 4-((3-chloro-4- fluorophenyl)sulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6- yl)carbamate 628.2 (M + Na)⁺ 10B

(S)-1,1,1-trifluoro-2-methylpropan-2- yl (2- (((benzyloxy)carbonyl)aminomethyl)- 4-((4-fluorophenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 626.3 (M + H)⁺ 10C

(S)-tert-butyl (2- (((methoxy)carbonyl)aminomethyl)- 4-((4-fluorophenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 440.1 (M-tBu + H)⁺ 10D

(S)-tert-butyl (4-((4- fluorophenyl)sulfonyl)-2-((3- methylureido)methyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6- yl)carbamate 439.0 (M-tBu + H)⁺ 10E

(S)-1,1,1-trifluoro-2-methylpropan-2- yl (2-((3-cyclopropylureido)methyl)- 4-((4-fluorophenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 575.2 (M + H)⁺ 10F

(S)-1,1,1-trifluoro-2-methylpropan-2- yl (2-((3-cyclobutylureido)methyl)-4- ((4-fluorophenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 589.1 (M + H)⁺ 10G

(S)-1,1,1-trifluoro-2-methylpropan-2- yl (2-((3-(tert-butyl)ureido)methyl)- 4-((4-fluorophenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 591.1 (M + H)⁺ 10H

(S)-1,1,1-trifluoro-2-methylpropan-2- yl (4-((4-fluorophenyl)sulfonyl)-2- ((3-isopropylureido)methyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 577.1 (M + H)⁺ 10i

(S)-1,1,1-trifluoro-2-methylpropan-2- yl (4-((4-fluorophenyl)sulfonyl)-2- ((3-(thiophen-3-yl)ureido)methyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin- 6-yl)carbamate 617.1 (M + H)⁺ 10J

(S)-1,1,1-trifluoro-2-methylpropan-2- yl (2-((3-ethylureido)methyl)-4-((4- fluorophenyl)sulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6- yl)carbamate 563.1 (M + H)⁺ 10K

(S)-1,1,1-trifluoro-2-methylpropan-2- yl (2-((3-cyclohexylureido)methyl)-4- ((4-fluorophenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 617.0 (M + H)⁺

Example 11 Synthesis of (R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (11)

Part 1—Synthesis of (R)-tert-butyl (2-((5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R)-tert-butyl (2-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (200 mg, 0.713 mmol), triphenylphosphine (187 mg, 0.713 mmol), 2-methyl-1,2,5-thiadiazolidine 1,1-dioxide (97 mg, 0.713 mmol), and toluene (3567 μL) was added diisopropyldiazodicarboxylate (146 μL, 0.749 mmol). The reaction was stirred at 50° C. for two hours. The mixture was partitioned between ethyl acetate and saturated NaHCO₃. The organic layer was washed with brine, dried (MgSO₄), and concentrated. The residue was purified by MPLC eluting with a gradient of 0-100% ethyl acetate in hexanes to afford the title compound: LCMS (ESI) calculated for C₁₇H₂₇N₄O₅S (M+H)⁺: 399. Found: 399.

Part 2—Synthesis of (R)-tert-butyl (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A solution of (R)-tert-butyl (2-((5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (148.5 mg, 0.373 mmol), 3-chloro-4-fluorobenzene-1-sulfonyl chloride (171 mg, 0.745 mmol), and pyridine (1863 μL) was heated at 50° C. overnight. The mixture was cooled, and partitioned between ethyl acetate and saturated NaHCO₃. The organic layer was washed with brine, dried (MgSO₄), and concentrated. The residue was purified via MPLC eluting with a gradient of 0-100% ethyl acetate in hexanes to afford the title compound: LCMS (ESI) calculated for C₁₉H₂₀ClFN₄O₇S₂ (M-tBu+H)⁺: 535. Found: 535.

Part 3—Synthesis of (R)-2-((6-amino-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)-5-methyl-1,2,5-thiadiazolidine 1,1-dioxide

A solution of (R)-tert-butyl (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (208 mg, 0.352 mmol), HCl (1760 μL, 7.04 mmol), and THF (1760 μL) was heated at 50° C. for three days. The mixture was cooled and concentrated to afford the title compound: LCMS (ESI) calculated for C₁₈H₂₁ClFN₄O₅S₂ (M+H)⁺: 491. Found: 491.

Part 4—Synthesis of (R)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A solution of (R)-2-((6-amino-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)-5-methyl-1,2,5-thiadiazolidine 1,1-dioxide (173 mg, 0.352 mmol), 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (133 mg, 0.599 mmol), and DMF (1762 μL) was heated at 100° C. for two hours. The reaction was partitioned between ethyl acetate and saturated NaHCO₃. The organic layer was washed with brine, dried (MgSO₄), and concentrated. The residue was purified via MPLC eluting with a gradient of 0-100% ethyl acetate in hexanes to afford the title compound: LCMS (ESI) calculated for C₂₃H₂₆ClF₄N₄O₇S₂ (M+H)⁺: 645. Found: 645. ¹H NMR: (300 MHz, CDCl₃): δ 9.78 (1H, s), 8.07 (1H, d, J=7.19 Hz), 7.92 (1H, s), 7.75 (1H, m), 7.64 (1H, t, J=10.79 Hz), 7.14 (1H, d, J=7.2 Hz), 6.80 (1H, d, J=10.79 Hz), 4.39 (1H, d, J=14.32 Hz), 3.71 (1H, m), 3.63 (1H, t, J=7.16 Hz), 3.20 (2H, m), 2.60 (3H, s), 1.73 (1H, m), 1.70 (6H, s), 1.52 (1H, m), 1.31 (2H, m).

Example 12 Synthesis of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((4-fluorophenyl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (12)

To a stirred mixture of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (50 mg, 0.102 mmol), methylsulfamoyl chloride (13.18 mg, 0.102 mmol), and dichloromethane (1017 μL was added N,N′-diisopropylethylamine (26.7 μL, 0.153 mmol) at room temperature. After twenty hours, the mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was dried (MgSO₄) and concentrated. The residue was dissolved in DMSO (1.5 mL), filtered and purified by reverse phase chromatography to afford the title compound. LRMS (ESI) calculated for C₂₁H₂₅F₄N₄O₇S₂ (M+H)+: 585. Found: 585. ¹H NMR (300 MHz, CDCl₃) δ 9.77 (1H, s), 7.90 (1H, s), 7.77 (2H, m), 7.41 (2H, t, J=7.99 Hz), 7.19 (2H, m), 6.79 (1H, m), 6.76 (1H, d, J=8.71 Hz), 4.38 (1H, m), 3.52 (1H, m), 3.22 (1H, m), 3.00 (2H, m), 2.41 (3H, m), 1.69 (6H, m).

Example 13 Additional Sulfamides of Aminobenzoxazines

The compounds in Table 4 below were prepared based on the experimental procedures described in Examples 11 and 12 and elsewhere in the detailed description utilizing the appropriate sulfamoyl halide, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 4 Ex. Observed No. Structure Name m/z 13A

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((4-fluorophenyl)sulfonyl)-2- ((morpholine-4-sulfonamido)methyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 641.3 (M + H)⁺ 13B

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(((N,N- diethylsulfamoyl)amino)methyl)-4-((4- fluorophenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 627.2 (M + H)⁺ 13C

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(((N,N- dimethylsulfamoyl)amino)methyl)-4- ((4-fluorophenyl)sulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6-yl)carbamate 599.1 (M + H)⁺ 13D

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((4-fluorophenyl)sulfonyl)-2- ((piperidine-1-sulfonamido)methyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 639 (M + H)⁺ 13E

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((4-fluorophenyl)sulfonyl)-2- ((pyrrolidine-1-sulfonamido)methyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 625 (M + H)⁺ 13F

1,1,1-trifluoro-2-methylpropan-2-yl ((2S)-4-((4-fluorophenyl)sulfonyl)-2- ((2-methylpiperidine-1- sulfonamido)methyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 653 (M + H)⁺ 13G

1,1,1-trifluoro-2-methylpropan-2-yl ((2S)-2-((2,6-dimethylmorpholine-4- sulfonamido)methyl)-4-((4- fluorophenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 669 (M + H)⁺ 13H

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((4-fluorophenyl)sulfonyl)-2-((4- methylpiperidine-1- sulfonamido)methyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 653 (M + H)⁺ 13i

1,1,1-trifluoro-2-methylpropan-2-yl ((2S)-4-((4-fluorophenyl)sulfonyl)-2- ((2-methylmorpholine-4- sulfonamido)methyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 655 (M + H)⁺ 13J

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(((N-cyclopropyl-N- methylsulfamoyl)amino)methyl)-4-((4- fluorophenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 625 (M + H)⁺ 13K

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(((N-cyclopentyl-N- methylsulfamoyl)amino)methyl)-4-((4- fluorophenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 653 (M + H)⁺ 13L

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((4-fluorophenyl)sulfonyl)-2-(((N- methyl-N-(2,2,2- trifluoroethyl)sulfamoyl)amino)methyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 667 (M + H)⁺ 13M

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((3-chloro-4-fluorophenyl)sulfonyl)- 2-(((N-methylsulfamoyl)amino)methyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 619.5 (M + H)⁺ 13N

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((3-chloro-4-fluorophenyl)sulfonyl)- 2-((piperidine-1-sulfonamido)methyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 673 (M + H)⁺ 13o

1,1,1-trifluoro-2-methylpropan-2-yl ((2S)-4-((3-chloro-4- fluorophenyl)sulfonyl)-2-((2- methylpiperidine-1- sulfonamido)methyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 687 (M + H)⁺ 13P

1,1,1-trifluoro-2-methylpropan-2-yl ((2S)-4-((3-chloro-4- fluorophenyl)sulfonyl)-2-((2- methylmorpholine-4- sulfonamido)methyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 689 (M + H)⁺ 13Q

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((3-chloro-4-fluorophenyl)sulfonyl)- 2-(((N-methyl-N-(2,2,2- trifluoroethyl)sulfamoyl)amino)methyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 701 (M + H)⁺ 13R

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((3-chloro-4-fluorophenyl)sulfonyl)- 2-(((N-isobutyl-N- methylsulfamoyl)amino)methyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 675 (M + H)⁺ 13S

1,1,1-trifluoro-2-methylpropan-2-yl ((2S)-4-((3-chloro-4- fluorophenyl)sulfonyl)-2-((3- methylpyrrolidine-1- sulfonamido)methyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 688 (M + H)⁺ 13T

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((3-chloro-4-fluorophenyl)sulfonyl)- 2-(((N-ethylsulfamoyl)amino)methyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 633.0 (M + H)⁺ 13U

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((3-chloro-4-fluorophenyl)sulfonyl)- 2-(((N- isopropylsulfamoyl)amino)methyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 647.0 (M + H)⁺ 13V

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(((N-ethylsulfamoyl)amino)methyl)- 4-((4-fluorophenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 599.1 (M + H)⁺ 13W

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((4-fluorophenyl)sulfonyl)-2-(((N- isopropylsulfamoyl)amino)methyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 613.1 (M + H)⁺ 13X

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(((N-(tert- butyl)sulfamoyl)amino)methyl)-4-((4- fluorophenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 627.1 (M + H)⁺ 13Y

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((3,4-difluorophenyl)sulfonyl)-2- (((N-methylsulfamoyl)amino)methyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 603.1 (M + H)⁺ 13Z

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((3-ethoxy-1-ethyl-1H-pyrazol-4- yl)sulfonyl)-2-(((N- methylsulfamoyl)amino)methyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 629.1 (M + H)⁺ 13AA

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((1-ethyl-3-methyl-1H-pyrazol-4- yl)sulfonyl)-2-(((N- methylsulfamoyl)amino)methyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 599.1 (M + H)⁺ 13AB

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((3-chloro-1-ethyl-1H-pyrazol-4- yl)sulfonyl)-2-(((N- methylsulfamoyl)amino)methyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 619.1 (M + H)⁺ 13AC

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((3-(2,2-difluoroethoxy)-1-ethyl-1H- pyrazol-4-yl)sulfonyl)-2-(((N- methylsulfamoyl)amino)methyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 665.1 (M + H)⁺ 13AD

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((1-(2,2-difluoroethyl)-3-ethoxy-1H- pyrazol-4-yl)sulfonyl)-2-(((N- methylsulfamoyl)amino)methyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 665.1 (M + H)⁺ 13AE

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((1-(difluoromethyl)-3-methyl-1H- pyrazol-4-yl)sulfonyl)-2-(((N- methylsulfamoyl)amino)methyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 621.1 (M + H)⁺ 13AF

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((2-methoxy-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-3-yl)sulfonyl)-2- (((N-methylsulfamoyl)amino)methyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 627.1 (M + H)⁺ 13AG

2,2,2-trifluoro-1,1-dimethylethyl [(2S)-4- {[1-(difluoromethyl)-3-(2- hydroxyethoxy)-1H-pyrazol-4- yl]sulfonyl}-2- {[(methylsulfamoyl)amino]methyl}- 3,4-dihydro-2H-1,4-benzoxazin-6- yl]carbamate 667 (M + H)⁺

Example 14 Synthesis of (R)-tert-butyl (2-((pyridin-2-ylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (14)

To (R)-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl methanesulfonate (150 mg, 0.265 mmol) and cesium carbonate (431 mg, 1.32 mmol) in DMF (1 mL) at room temperature was added pyridine-2-thiol (147 mg, 1.32 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaHCO₃, water, brine, dried (Na₂SO₄) and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate/hexane (0˜25%) to give (R)-tert-butyl (2-((pyridin-2-ylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate as white solid. LRMS (ESI) calculated for C₂₆H₂₆F₃N₃O₅S₂ (M+H)⁺: 582. Found 582. ¹H NMR (600 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.41 (dd, J=39.2, 4.0 Hz, 1H), 8.05-7.72 (m, 4H), 7.65-7.56 (m, 2H), 7.37-7.19 (m, 1H), 7.19-6.97 (m, 2H), 6.71 (d, J=8.9 Hz, 1H), 4.40 (dd, J=14.2, 2.2 Hz, 1H), 3.60 (s, 1H), 3.45-3.38 (m, 2H), 3.15-3.20 (m, 1H) 1.43 (s, 9H).

Example 15 Preparation of additional (R)-tert-butyl (2-((thioalkyl or thioaryl or thioheteroaryl)methyl)-4-((3-(trffluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamates

The compounds in Table 5 below were prepared based on the experimental procedures described in Example 14 and elsewhere in the detailed description using the appropriate thiol in place of pyridine-2-thiol, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 5 Ex. No. Structure Name Observed m/z 15A

(R)-tert-butyl (2- ((cyclopentylthio)methyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 595.0 (M + Na)⁺ 15B

(R)-tert-butyl (2-((benzylthio)methyl)-4- ((3-(trifluoromethyl)phenyl)sulfonyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 617.0 (M + Na)⁺ 15C

(R)-tert-butyl (2-((tert-butylthio)methyl)- 4-((3-(trifluoromethyl)phenyl)sulfonyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 583.0 (M + Na)⁺ 15D

(R)-tert-butyl (2-(((4,5-dimethyl-1H- imidazol-2-yl)thio)methyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 599.1 (M + H)⁺ 15E

(R)-tert-butyl (2-((phenylthio)methyl)-4- ((3-(trifluoromethyl)phenyl)sulfonyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 525.0 (M-tBu + H)⁺ 15F

(R)-tert-butyl (2-((methylthio)methyl)-4- ((3-(trifluoromethyl)phenyl)sulfonyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 540.8 (M + Na)⁺

Example 16 Synthesis of (R)-tert-butyl (2-((pyridin-2-ylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (16)

To a solution of (R)-tert-butyl (2-((pyridin-2-ylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (100 mg, 0.172 mmol) in dichloromethane (5 mL) was added meta-chloroperbenzoic acid (148 mg, 0.860 mmol) and the mixture was stirred at room temperature for three hours. The mixture was concentrated and purified by silica gel chromatography using a gradient of ethyl acetate/hexane (0˜50%), to give (R)-tert-butyl (2-((pyridin-2-ylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate as a white solid. ¹H NMR (600 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.69 (d, J=4.7 Hz, 1H), 8.19-7.68 (m, 7H), 6.89 (d, J=8.9 Hz, 1H), 5.99 (d, J=8.9 Hz, 1H), 4.40 (dd, J=14.1, 2.3 Hz, 1H), 4.01-3.79 (m, 3H), 3.50 (dd, J=14.2, 9.0 Hz, 1H), 1.42 (s, 9H).

Example 17 Preparation of additional (2-((alkyl or aryl or heteroaryl sulfonyl)methyl)-benzoxazines

The compounds in Table 6 below were prepared based on the experimental procedures described in Example 16 and elsewhere in the detailed description, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 6 Ex. No. Structure Name Observed m/z 17A

(R)-tert-butyl (2-((tert- butylsulfonyl)methyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 615.0 (M + Na)⁺ 17B

(R)-tert-butyl (2-(((4,5-dimethyl-1H- imidazol-2-yl)sulfonyl)methyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 631.0 (M + H)⁺ 17C

(R)-tert-butyl (2- ((phenylsulfonyl)methyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 635.0 (M + Na)⁺ 17D

(R)-tert-butyl (2- ((cyclopentylsulfonyl)methyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 549.2 (M-tBu + H)⁺ 17E

(R)-tert-butyl (2- ((benzylsulfonyl)methyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 644.2 (M + NH₄)⁺ 17F

(R)-tert-butyl (2- ((methylsulfonyl)methyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 572.8 (M + Na)⁺

Example 18 Synthesis of (R)-tert-butyl (2-((pyridin-2-ylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (18)

The title compound was prepared according to the procedures described below.

Part I—Synthesis of (R)-tert-butyl (2-((benzylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a suspension of sodium hydride (78 mg, 1.942 mmol) in DMF (1 mL) at room temperature was added phenylmethanethiol (0.233 mL, 1.942 mmol) and the mixture was stirred at room temperature for ten minutes. Then a solution of (R)-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl methanesulfonate (550 mg, 0.971 mmol) in DMF (4 mL) was added and the stirring continued at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with bleach, water and brine subsequently, then dried (Na₂SO₄) and concentrated. The residue was purified on silica chromatograph (40 g) and eluted with a gradient of ethyl acetate/hexane (0˜25%) to give (R)-tert-butyl (2-((benzylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate as light yellow solid. LRMS (ESI) calculated for C₂₈H₂₉F₃N₂O₅S₂ (M+H)⁺: 595. Found: 539 (M-tBu+H)⁺ and 617 (M+Na)⁺.

Part II—Synthesis of (R)-tert-butyl (2-((chlorosulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R)-tert-butyl (2-((benzylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (50 mg, 0.084 mmol) in acetic acid (1 mL)/water (0.33 mL) at room temperature was added N-chlorosuccinimide (33.7 mg, 0.252 mg) and the mixture was stirred at room temperature for 2.5 hours. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium thiosulfate, water and brine, then dried (Na₂SO₄) and concentrated to give the crude product (R)-tert-butyl (2-((chlorosulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate. LRMS (ESI) calculated for C₂₁H₂₂ClF₃N₂O₇S₂ (M+H)⁺: 571. Found: 515 (M-tBu+H)⁺ and 593 (M+Na)⁺.

Part III—Synthesis of (R)-tert-butyl (2-((pyridin-2-ylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R)-tert-butyl (2-((chlorosulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamatemate (50 mg, 0.084 mmol) in dichloromethane (50 mg, 0.088 mmol) at room temperature was added methylamine hydrochloride (0.219 mL, 0.438 mmol) followed by triethyl amine (0.037 mL, 0.263 mmol) and the mixture was stirred at room temperature for an hour. The solvent was concentrated and the residue was purified via MPLC eluting with an ethyl acetate/hexanes gradient (0-50%) to afford (R)-tert-butyl (2-((pyridin-2-ylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate. LRMS (ESI) calculated for C₂₂H₂₆F₃N₃O₇S₂ (M+H)⁺: 566. Found: 510 (M-tBu)⁺ and 588 (M+Na)⁺. ¹H NMR (600 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.04 (dd, J=33.5, 7.6 Hz, 4H), 7.82 (t, J=8.0 Hz, 1H), 7.03 (dd, J=13.1, 7.3 Hz, 2H), 6.74 (d, J=8.9 Hz, 1H), 4.49 (d, J=14.0 Hz, 1H), 3.84 (s, 1H), 3.51-3.37 (m, 2H), 3.29 (dd, J=14.7, 7.1 Hz, 1H), 2.50 (s, 3H), 1.44 (s, 9H).

Example 19 Preparation of additional reverse 2-alkyl sulfonamide benzoxazines

The compounds in Table 7 below were prepared based on the experimental procedures described in Example 18 and elsewhere in the detailed description, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 7 Ex. No. Structure Name Observed m/z 19A

(R)-tert-butyl (2-((N- cyclopropylsulfamoyl)methyl)-4- ((3-(trifluoromethyl) phenyl)sulfonyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 535.9 (M-tBu + H)⁺ 19B

(R)-tert-butyl (2-((N-(2,2,2- trifluoroethyl)sulfamoyl) methyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 655.9 (M + Na)⁺ 19C

(R)-tert-butyl (2- ((morpholinosulfonyl) methyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 566.0 (M-tBu + H)⁺ 19D

(R)-tert-butyl (2-((N- ethylsulfamoyl)methyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 602.0 (M + Na)⁺ 19E

(R)-tert-butyl (2-((N,N- dimethylsulfamoyl)methyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 523.9 (M-tBu + H)⁺

Example 20 Synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl(S)-(4-((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (20)

Part 1—Synthesis of 1-ethyl-1,2-dihydro-3H-pyrazol-3-one

To methyl 2-chloroprop-2-enoate (5 mL, 49.8 mmol) in anhydrous tetrahydrofuran (75 mL) was added ethylhydrazine oxalate (11.2 g, 74.7 mmol) followed by triethylamine (13.9 mL, 99.6 mmol). The reaction was stirred at ambient temperature overnight. The solids were filtered off, then the filtrates were concentrated. The residue was purified by column chromatography eluting with a gradient of methanol in dichloromethane. The pure fractions were combined and concentrated in vacuo to yield the title compound.

Part 2—Synthesis of 3-ethoxy-1-ethyl-1H-pyrazole

To a solution of 1-ethyl-1,2-dihydro-3H-pyrazol-3-one (1.55 g, 13.8 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (3.8 g, 27.6 mmol) followed by ethyl bromide (2.1 mL, 27.6 mmol). The reaction was stirred at ambient temperature for 3 hours. The solution was diluted with ethyl acetate, washed with water, brine, dried with sodium sulfate, filtered and concentrated in vacuo to yield the title compound.

Part 3—Synthesis of 3-Ethoxy-1-ethyl-1H-pyrazole-4-sulfonyl chloride

To 3-ethoxy-1-ethyl-1H-pyrazole (3.14 g, 22.4 mmol) in chloroform (25 mL) at 0° C. was added chlorosulfonic acid (15 mL, 224 mmol) dropwise. The resulting solution was stirred for 3 hours at 70° C. The solution was cooled in an ice bath and then quenched by pouring into ice water. The resulting suspension was extracted with dichloromethane and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to yield the title compound as an oil.

Part 4—Synthesis of Methyl (S)-2-(4-bromo-2-nitrophenoxy)propanoate

To a solution of 5-bromo-2-fluoronitrobenzene (5.4 g, 24.5 mmol) in tetrahydrofuran (50 mL) at 0° C. was added (S)-lactic acid methyl ester (3.1 g, 29.4 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (4.4 mL, 26.9 mmol). The cooling bath was removed and reaction was stirred at ambient temperature overnight. The solution was partitioned between ethyl acetate and water, washed with water, brine, dried with sodium sulfate, filtered and concentrated in the presence of silica. The residue was purified by column chromatography eluting with a gradient of 0-60% ethyl acetate in hexanes. The pure fractions were combined and concentrated in vacuo to yield the title compound.

Part 5—Synthesis of (S)-6-Bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one

To methyl (S)-2-(4-bromo-2-nitrophenoxy)propanoate (2.4 g, 7.9 mmol) in acetic acid (30 mL) was added powdered iron (2.2 g, 39.5 mmol) and the reaction was heated to 70° C. for 2 hours. The warm suspension was filtered through CELITE, and washed with ethyl acetate. The filtrates were partitioned between ethyl acetate and water, washed with water, brine, dried with sodium sulfate, filtered and concentrated in vacuo to yield the title compound.

Part 6—Synthesis of (S)-6-Bromo-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a solution of (S)-6-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (1.55 g, 6.4 mmol) in anhydrous tetrahydrofuran (20 mL) under a nitrogen atmosphere at ambient temperature was carefully added borane-methyl sulfide complex (2.56 mL, 25.6 mmol). The reaction was then refluxed for 90 minutes, cooled in an ice bath and quenched with methanol (20 mL). The suspension was next heated to reflux for 20 minutes, then concentrated in vacuo. The residue was partitioned between ethyl acetate and water, washed with brine, dried with sodium sulfate, filtered and concentrated in vacuo to yield the title compound.

Part 7—Synthesis of (S)-6-Bromo-4-((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine

A mixture of (S)-6-bromo-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.5 g, 2.2 mmol), 3-ethoxy-1-ethyl-1H-pyrazole-4-sulfonyl chloride (0.63 g, 2.6 mmol) and pyridine (8 mL) was stirred at 70° C. overnight. The solution was cooled, diluted with ethyl acetate, washed with 10% citric acid, brine, dried (Na₂SO₄). To the suspension was added activated charcoal and the suspension was slurried. The mixture was filtered through CELITE and concentrated. The residue was purified by column chromatography eluting with a gradient of ethyl acetate in hexanes to yield the title compound.

Part 8—Synthesis of 1,1,1-Trifluoro-2-methylpropan-2-yl (S)-(4-((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

In toluene (4 mL) and water (1 mL) was combined (S)-6-bromo-4-((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.2 g, 0.47 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (22 mg, 0.046 mmol), tert-butyl carbamate (0.11 g, 0.93 mmol) and tripotassium phosphate (0.3 g, 1.4 mmol) followed by the addition of tris(dibenzylideneacetone)dipalladium(0) (21 mg, 0.046 mmol) and heated at 100° C. overnight. The cooled solution was partitioned between ethyl acetate and water, washed with brine, dried (Na₂SO₄), and concentrated. The mixture was purified by column chromatography eluting with a gradient of ethyl acetate in hexanes. To the intermediate was added was added 4M hydrogen chloride in dioxane (3 mL) and the result was stirred at ambient temperature for 1 hour. The resulting suspension was concentrated. The residue was redissolved in N,N-dimethylformamide (2 mL) and combined with (2,2,2-trifluoro-1,1-dimethyl-ethyl) imidazole-1-carboxylate (0.097 g, 0.44 mmol). The mixture was heated to 100° C. in the microwave for 2 hours. The cooled solution was partitioned between ethyl acetate and water, washed with brine, dried (Na₂SO₄), and concentrated. The residue was purified by column chromatography eluting with a gradient of 70-100% ethyl acetate in hexanes to afford the title compound. LCMS (ESI) calculated for C₂₁H₂₈F₃N₄O₆S (M+H)⁺: 521. Found: 521.

Example 21 Synthesis of [(2S,3S and 2R,3R)-4-(3-cyano-benzenesulfonyl)-2-hydroxymethyl-3-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic acid 2,2-dimethyl-propyl ester (21)

The title compound was prepared according to the procedures described below.

Part I—Synthesis of N-(but-3-en-2-yl)-3-cyano-N-(2-fluoro-5-nitrophenyl)-benzenesulfonamide

To a mixture of 3-cyano-N-(2-fluoro-5-nitro-phenyl)-benzenesulfonamide (2.8 g, 8.7 mmol), 3-buten-2-ol (0.626 g, 8.8 mmol) and triphenylphosphine was added diisopropyldiazodicarboxylate (2.28 g, 9.6 mmol) in THF (50 mL) dropwise at 0° C. After this addition, the mixture was warmed to room temperature and stirred overnight. The solvent was removed and the resulting residue purified by silica gel chromatography (dichloromethane) to provide N-(but-3-en-2-yl)-3-cyano-N-(2-fluoro-5-nitrophenyl) benzenesulfonamide. LRMS (ESI) calculated for C₁₇H₁₆FN₃O₄S (M+H)⁺: 376. Found: 376.2.

Part II—Synthesis of 3-cyano-N-(2,3-dihydroxy-1-methyl-propyl)-N-(2-fluoro-5-nitro-phenyl)-benzenesulfonamide

To a mixture of 3-cyano-N-(2-fluoro-5-nitro-phenyl)-N-(1-methyl-allyl)-benzenesulfonamide (2.6 g, 6.9 mmol), N-methylmorpholine N-oxide (0.97 g, 8.3 mmol) in acetone (20 mL) and water (40 mL) was added osmium tetroxide (0.3 g). The mixture was stirred overnight at room temperature and diluted with water (50 mL). White precipitate was filtered, washed with water and hexanes to provide a mixture of diastereomers of 3-cyano-N-(2,3-dihydroxy-1-methyl-propyl)-N-(2-fluoro-5-nitro-phenyl)-benzenesulfonamide. LRMS (ESI) calculated for C₁₇H₁₇FN₃O₆S (M+H)⁺: 410. Found 410.3.

Part III—Synthesis of 3-((2S,3S and 2R,3R)-2-hydroxymethyl-3-methyl-6-nitro-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-benzonitrile

A mixture of 3-((2S,3S and 2R,3R)-2-hydroxymethyl-3-methyl-6-nitro-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-benzonitrile (2.5 g, 6.4 mmol), sodium hydride (0.56 g, 22.4 mmol) in THF (100 mL) was heated to reflux for three days. The mixture was cooled to 0° C. and quenched with 2N HCl, diluted with ethyl acetate, washed with water, saturated sodium bicarbonate, and concentrated. The residue was purified by silica gel chromatography (hexanes/ethyl acetate, 1.5/1) to provide 3-((2S,3S and 2R,3R)-2-hydroxymethyl-3-methyl-6-nitro-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-benzonitrile. LRMS (ESI) calculated for C₁₇H₁₆N₃O₄S (M+H)⁺: 390. Found: 390.1.

Part IV—Synthesis of 3-((2S,3S and 2R,3R)-6-amino-2-hydroxymethyl-3-methyl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-benzonitrile

A mixture of 3-((2S,3S and 2R,3R)-2-hydroxymethyl-3-methyl-6-nitro-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-benzonitrile (2.5 g, 6.11 mmol), iron (1.0 g) in dioxane (50 mL) and 6N HCl (20 mL) was heated to reflux for three hours. After the mixture was cooled, saturated sodium bicarbonate and ethyl acetate (200 mL) were added. The layers were partitioned and the organic layer was washed with brine and separated, dried (Na₂SO₄) and concentrated. The residue was chromatographed on silica gel to give desired product. LRMS (ESI) calculated for C₁₇H₁₈N₃O₂S (M+H)⁺: 360. Found: 360.3.

Part V—Synthesis of [(2S,3S and 2R,3R)-4-(3-cyano-benzenesulfonyl)-2-hydroxymethyl-3-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic acid 2,2-dimethyl-propyl ester

3-((2S,3S and 2R,3R)-6-Amino-2-hydroxymethyl-3-methyl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-benzonitrile (89.8 mg, 0.25 mmol) was treated with neopentyl chloroformate by the procedures described above to give the title compound. LRMS (ESI) calculated for C₂₃H₂₈N₃O₆S (M+H)⁺: 474. Found: 474.

Example 22 Synthesis of (S and R)-1,1,1-trifluoro-2-methylpropan-2-yl 4-(4-fluorophenylsulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylcarbamate (Example Nos. 22A and 22B)

Step 1—Preparation of 3-methyl-6-nitro-2H-benzo[b][1,4]oxazine

A mixture of 1-chloropropan-2-one (3.4 g, 30 mmol) and K₂CO₃ (8.3 g, 60 mmol) in acetone (100 mL) was stirred for 10 minutes at room temperature. Then 2-amino-4-nitrophenol (5 g, 30 mmol) was added and the reaction mixture was stirred for 12 hours at 80° C. The reaction mixture was cooled to 20° C., filtered, concentrated in vacuo and purified by crystallization with MeOH/petroleum ether (10:1) to afford the title compound as a yellow solid. LCMS (ESI): calculated for C₉H₈N₂O₃ [M+H]⁺: 193. found: 193.

Step 2—Preparation of 3-methyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a solution of 3-methyl-6-nitro-2H-benzo[b][1,4]oxazine (300 mg, 1.568 mmol) in ethanol (10 mL) was added NaBH₄ (71 mg, 1.87 mmol). The mixture was stirred at room temperature for an hour. The reaction was quenched with water and extracted three times with EtOAc (50 mL each). The combined organic layers were washed with brine, dried (Na₂SO₄), filtered and concentrated to afford the title compound as a yellow solid. LCMS (ESI): calculated for C₉H₁₀N₂O₃(M+H)⁺: 195. found: 195.

Step 3—Preparation of 4-((4-fluorophenyl)sulfonyl)-3-methyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a solution of 3-methyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (300 mg, 1.55 mmol) in pyridine (4 mL) was added 4-fluorobenzene-1-sulfonyl chloride (1.5 g, 7.73 mmol). The reaction was stirred at 100° C. for 12 hours and diluted with water (10 mL). The mixture was extracted three times with ethyl acetate (50 mL each). The combined organic layers were dried (Na₂SO₄) and concentrated. The residue was crystallized with 1% methanol in ethyl acetate to give the title compound. LCMS (ESI): calculated for C₁₅H₁₃FN₂O₅S (M+H)⁺: 353. found: 353.

Step 4—Preparation of 4-((4-fluorophenyl)sulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine

The atmosphere above a solution of 4-((4-fluorophenyl)sulfonyl)-3-methyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (250 mg, 0.71 mmol) in ethyl acetate (50 mL) was purged with nitrogen and 10% Pd/C (0.3 g) was added. The atmosphere was then replaced with hydrogen and stirred at 25° C. for 12 hours. The mixture was filtered through a CELITE pad, the pad was washed with ethyl acetate, and the combined filtrates were concentrated to afford the title compound as a yellow solid. LCMS (ESI): calculated for C₁₅H₁₅FN₂O₃S (M+H)⁺: 323. found: 323.

Step 5—Preparation of (S and R)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((4-fluorophenyl)sulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A mixture of 4-nitrophenyl (1,1,1-trifluoro-2-methylpropan-2-yl) carbonate (136 mg, 0.46 mmol) and 4-((4-fluorophenyl)sulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine (100 mg, 0.31 mmol) in N,N-diisopropylethylamine (1.5 mL) was heated at 100° C. for 16 hours. The reaction mixture was cooled and diluted with 1 M HCl (20 mL). The mixture was extracted three times with EtOAc (50 mL each). The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated. The residue was purified by prep-TLC eluting with petroleum ether:ethyl acetate (3:1) to afford the title compound as a yellow solid, which was further separated by SFC (Column: Chiralpak AD-3 150×4.6 mm I.D., 3 um Mobile phase: methanol (0.05% DEA) in CO₂ from 5% to 40% Flow rate: 2.5 mL/min Wavelength: 220 nm) to give two isomers. LCMS (ESI): calculated for C₂₀H₂₀F₄N₂O₅S (M+H)⁺: 477. found: 477.

Example 23 Synthesis of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((4-fluorophenyl)sulfonyl)-3-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Example Nos. 23A and 23B)

Step 1—Preparation of N-(2-(allyloxy)-5-nitrophenyl)-4-fluorobenzenesulfonamide

To a solution of NaH (417 mg, 9.55 mmol) in THF (5 mL) was added prop-2-en-1-ol (554 mg, 9.55 mmol) in THF (5 mL), and the reaction mixture was stirred at 0° C. for 20 minutes. Then 4-fluoro-N-(2-fluoro-5-nitrophenyl)benzenesulfonamide (1.0 g, 3.18 mmol) in THF (10 mL) was added to the reaction mixture and the resulting mixture was stirred at 0° C. for 3 hours. The reaction was quenched with 1 N HCl (10 mL). The mixture was partitioned between and ethyl acetate and water. The organic layer was washed with brine, dried (Na₂SO₄) and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate (4:1) to afford the title compound.

Step 2—Preparation of 4-fluoro-N-(5-nitro-2-(oxiran-2-ylmethoxy)phenyl) benzenesulfonamide

A mixture of N-(2-(allyloxy)-5-nitrophenyl)-4-fluorobenzenesulfonamide (600 mg, 1.7 mmol) and m-CPBA (441 mg, 2.55 mmol) in dichloroethane (15 mL) was stirred at 90° C. overnight. The mixture was cooled and concentrated. The residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (Na₂SO₄) and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate (2:1) to afford the title compound.

Step 3—Preparation of (4-((4-fluorophenyl)sulfonyl)-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methanol

Potassium carbonate (150 mg, 1.08 mmol) was added to 4-fluoro-N-(5-nitro-2-(oxiran-2-ylmethoxy) phenyl)benzenesulfonamide (100 mg, 0.27 mmol) in acetonitrile (2 mL). The reaction mixture was heated at 120° C. by microwave irradiation for 40 minutes. The reaction mixture was diluted with water, and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated. The residue was purified by prep-TLC eluting with petroleum ether:ethyl acetate (1:1) to afford the title compound.

Step 4—Preparation of (4-((4-fluorophenyl)sulfonyl)-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methyl acetate

A mixture of (4-((4-fluorophenyl)sulfonyl)-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methanol (170 mg, 0.46 mmol), triethylamine (140 mg, 1.38 mmol) and acetyl chloride (73 mg, 0.93 mmol) in dichloromethane (2 mL) was stirred at room temperature for 2 hours. The mixture was diluted with water, and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated to afford the title compound as a yellow solid.

Step 5—Preparation of (6-amino-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methyl acetate

A mixture of (4-((4-fluorophenyl)sulfonyl)-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methyl acetate (190 mg, 0.46 mmol) and 10% palladium on carbon (50 mg) in ethyl acetate (5 mL) was stirred under a hydrogen atmosphere (15 psi) overnight. The mixture was filtered through CELITE, the filter pad was washed with ethyl acetate, and the combined filtrates were concentrated to afford the title compound. LCMS (ESI): calculated for C₁₇H₁₇FN₂O₅S (M+H)⁺: 381. found: 381.

Step 6—Preparation of (4-((4-fluorophenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methyl acetate

A mixture of (6-amino-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methyl acetate (120 mg, 0.32 mmol) and 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (120 mg, 0.54 mmol) in DMSO (3 mL) was stirred at 80° C. overnight. The mixture was diluted with water, extracted with twice with ethyl acetate and the combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate (5:1) to afford the title compound. LCMS (ESI): calculated for C₂₂H₂₂F₄N₂O₇S (M+H)⁺: 535. found: 535.

Step 7—Preparation of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((4-fluorophenyl)sulfonyl)-3-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A mixture of (4-((4-fluorophenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methyl acetate (140 mg, 0.26 mmol) and potassium carbonate (310 mg, 2.23 mmol) in MeOH (4.5 mL) and water (0.5 mL) was stirred at room temperature for four hours. The reaction mixture was diluted with water, extracted with twice with ethyl acetate and the combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate (5:1) to afford the title compound, which was further separated by SFC (Column: Chiralpak AD-H 250×4.6 mm I.D., 5 um Mobile phase: methanol (0.05% DEA) in CO₂ from 5% to 40% Flow rate: 2.35 mL/min Wavelength: 220 nm) to give two isomers. LCMS (ESI): calculated for C₂₀H₂₀F₄N₂O₆S (M+H)⁺: 493. found: 493; ¹H NMR (400 MHz, CDCl₃) δ 7.82 (br s, 1H), 7.68 (dd, J=4.8, 8.4 Hz, 2H), 7.23 (d, J=8.0 Hz, 1H), 7.14 (t, J=8.4 Hz, 2H), 6.81 (br s, 1H), 6.76 (d, J=8.4 Hz, 1H), 4.39 (t, J=6.4 Hz, 1H), 4.13 (d, J=11.8 Hz, 1H), 3.62-3.68 (m, 1H), 3.51-3.58 (m, 1H), 3.18 (dd, J=2.4, 11.6 Hz, 1H), 1.76 (s, 6H).

Example 24 Synthesis of [(S)-4-(3-cyano-benzenesulfonyl)-2-(2,4-dioxo-oxazolidin-3-ylmethyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic acid tert-butyl ester (24)

To a solution of triphenylphosphine (1.2 g, 4.7 mmol) in tetrahydrofuran (7.5 mL) at 0° C. was added diisopropylazodicarboxylate (0.9 mL, 4.7 mmol). After fifteen minutes, [(R)-4-(3-cyano-benzenesulfonyl)-2-hydroxymethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic acid tert-butyl ester (1.4 g, 3.1 mmol) and 2,4-oxazolidinedione (0.3 g, 3.1 mmol) in tetrahydrofuran (7.5 mL) was added dropwise. After the addition was complete the mixture was allowed to warm to room temperature. The mixture was stirred an additional three hours, and partitioned between dichloromethane and 1 N HCl. The organic layer was dried (Na₂SO₄) and concentrated to afford [(S)-4-(3-cyano-benzenesulfonyl)-2-(2,4-dioxo-oxazolidin-3-ylmethyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic acid tert-butyl ester. LCMS ESI calculated for C₂₄H₂₅N₄O₈S (M+H)⁺: 529. Found: 529.

Example 25 Preparation of additional carbamates of 2-((2,4-dioxooxazolidin-3-yl)methyl)-benzoxazines

The compounds in Table 8 below were prepared based on the experimental procedures described in Example 24 and elsewhere in the detailed description, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 8 Ex. Observed No. Structure Name m/z 25A

(1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl ((S)- 4-((3-cyanophenyl)sulfonyl)-2-((2,4- dioxooxazolidin-3-yl)methyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6-yl)carbamate 584.2 (M + Na)⁺ 25B

(S)-neopentyl (4-((3- cyanophenyl)sulfonyl)-2-((2,4- dioxooxazolidin-3-yl)methyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6-yl)carbamate 543.1 (M + H)⁺ 25C

(1S,4R)-bicyclo[2.2.1]heptan-2-yl ((S)-2- ((2,4-dioxooxazolidin-3-yl)methyl)-4-((1- methyl-1H-pyrazol-4-yl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 563.2 (M + H₂O)⁺ 25D

(S)-tert-butyl (2-((2,4-dioxooxazolidin-3- yl)methyl)-4-((1-methyl-1H-pyrazol-4- yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 508 (M + H)⁺ 25E

(S)-neopentyl (2-((2,4-dioxooxazolidin-3- yl)methyl)-4-((1-methyl-1H-pyrazol-4- yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 522.1 (M + H)⁺ 25F

(tetrahydro-2H-pyran-2-yl)methyl ((S)-2- ((2,4-dioxooxazolidin-3-yl)methyl)-4-((1- methyl-1H-pyrazol-4-yl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 550.3 (M + H)⁺ 25G

(2S)-bicyclo[2.2.1]heptan-2-yl ((S)-4-((3- cyanophenyl)sulfonyl)-2-((2,4- dioxooxazolidin-3-yl)methyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6-yl)carbamate 567.1 (M + H)⁺ 25H

(2S)-bicyclo[2.2.1]heptan-2-yl ((S)-2-((2,4- dioxooxazolidin-3-yl)methyl)-4-((1- methyl-1H-pyrazol-4-yl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 546.1 (M + H)⁺

Example 26 Synthesis of [(S)-4-(3-cyano-benzenesulfonyl)-2-dimethylaminomethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic acid tert-butyl ester (26)

To a solution of toluene-4-sulfonic acid (R)-6-tert-butoxycarbonylamino-4-(3-cyano-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl ester (1.9 g, 3.2 mmol) in tetrahydrofuran (10 mL) was added dimethylamine (2 M in THF, 25 mL, 50 mmol) and the mixture was heated in a bomb at 100° C. overnight. The mixture was cooled and concentrated to afford [(S)-4-(3-cyano-benzenesulfonyl)-2-dimethylaminomethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic acid tert-butyl ester. LCMS (ESI): calculated for C₂₃H₂₉ClN₄O₅S (M+H)⁺: 473. Found 473.

Example 27 Synthesis of [(S)-4-(3-cyano-benzenesulfonyl)-2-dimethylaminomethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic acid 2,2-dimethyl-propyl ester (27)

The title compound was prepared according to the procedures described below.

Part I—Synthesis of 3-((S)-6-amino-2-dimethylaminomethyl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-benzonitrile

To a solution of [(S)-4-(3-cyano-benzenesulfonyl)-2-dimethylaminomethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic acid tert-butyl ester (3 mmol) in p-dioxane (5 mL) was added hydrochloric acid (4M in p-dioxane, 30 mL, 120 mmol). The mixture was stirred at room temperature for two hours. Additional 4M HCl in p-dioxane (10 mL) was added and the mixture allowed to stir for an additional two hours at room temperature. The mixture was quenched with saturated sodium bicarbonate, extracted into dichloromethane, then concentrated and purified by HPLC to obtain 3-((S)-6-amino-2-dimethylaminomethyl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-benzonitrile. LCMS (ESI): calculated for C₁₈H₂₁N₄O₃S (M+H)⁺: 373. Found: 373.

Part II—Synthesis of [(S)-4-(3-cyano-benzenesulfonyl)-2-dimethylaminomethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic acid 2,2-dimethyl-propyl ester

To a solution of 3-((S)-6-amino-2-dimethylaminomethyl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-benzonitrile (15 mg, 0.04 mmol) in pyridine (0.4 mL) was added neo-pentyl chloroformate (6.3 mg, 0.05 mmol) in dichloromethane (0.5 mL). The mixture was stirred at room temperature overnight. The reaction was quenched with a small amount of water and concentrated under vacuum. The resulting residue was diluted with DMSO and purified via HPLC to obtain [(S)-4-(3-cyano-benzenesulfonyl)-2-dimethylaminomethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic acid 2,2-dimethyl-propyl ester. LCMS (ESI): calculated for C₂₅H₂₇N₄O₈S (M+H)⁺: 543. Found: 543.

Example 28 Preparation of Additional Carbamates

The compounds in Table 9 below were prepared based on the methods described in Examples 26 and 27 and elsewhere in the detailed description, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 9 Ex. Observed No. Structure Name m/z 28A

(1S,4R)-bicyclo[2.2.1]heptan-2-yl ((S)-4-((3-cyanophenyl)sulfonyl)-2- ((dimethylamino)methyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 511.6 (M + H)⁺ 28B

(1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl ((S)-4-((3-cyanophenyl)sulfonyl)-2- ((dimethylamino)methyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 511.3 (M + H)⁺ 28C

(S)-neopentyl (2-((dimethylamino)methyl)- 4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 466.3 (M + H)⁺ 28D

bicyclo[2.2.1]heptan-2-yl ((S)-2- ((dimethylamino)methyl)-4-((1-methyl-1H- pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 490.3 (M + H)⁺ 28E

(2S)-bicyclo[2.2.1]heptan-2-yl ((S)-2- ((dimethylamino)methyl)-4-((1-methyl-1H- pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 490.3 (M + H)⁺ 28F

(S)-tetrahydro-2H-pyran-4-yl (4-((3- cyanophenyl)sulfonyl)-2- ((dimethylamino)methyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 499.3 (M + H)⁺

Example 29 Synthesis of (S)-methyl 2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate (29)

The title compound was prepared according to the procedures described below.

Part I—Synthesis of methyl 2-(6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate

To a stirred mixture of 2-amino-4-nitrophenol (5 g, 32.4 mmol), sodium bicarbonate (3.27 g, 38.9 mmol), and methanol (100 mL) was added a solution of methyl 4-bromocrotonate (3.82 mL, 32.4 mmol) in methanol (50 mL) dropwise during a 30 minute period. The reaction mixture was stirred an additional 18 hours at room temperature. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The organic layer was dried (MgSO₄) and concentrated. The residual oil was dissolved in ethanol (100 mL) and potassium carbonate (1.614 g, 11.68 mmol) was added. The reaction was stirred for 2.5 hours at room temperature and concentrated. The residue was partitioned between dichloromethane and water. The organic layer was extracted with 1 N HCl. The aqueous solution was neutralized with 1N NaOH and extracted with ethyl acetate. This organic layer was dried (Na₂SO₄) and concentrated to afford the title compound. LRMS ESI calculated for C₁₁H₁₃N₂O₅ (M+H)⁺: 253. Found: 253.

Part II—Synthesis of (R)- and (S)-methyl 2-(6-((tert-butoxycarbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate

To a stirred solution of methyl 2-(6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate (6.09 g, 24.15 mmol) and methanol (48 mL) purged with nitrogen was added 10% Pd/C (7.71 g, 7.24 mmol) followed by di-tert-butyl dicarbonate (6.73 mL, 29.0 mmol). The atmosphere above the reaction was purged and replaced with an atmosphere of hydrogen and was stirred at room temperature for 24 h. The crude mixture was filtered through CELITE, rinsing with methanol. The combined filtrates were concentrated. The residue was purified via MPLC eluting with a gradient of 0-100% ethyl acetate in hexanes. The racemic product was submitted for chiral SFC separation (SFC Column: Chiral Technology AZ-H 2.1×25 cm, 5 uM; MP: 30%/70% Ethanol/CO₂ (no other modifiers); Flow rate: 70 mL/Min, 6 min run time; WL: 220 nm; Injections of 0.30 ml were performed on the Berger Multigram II SFC). Mixture of Enantiomers LRMS ESI calculated for C₁₆H₂₃N₂O₅ (M+H)⁺: 323. Found: 323; (R)-Enantiomer: LRMS ESI calculated for C₁₆H₂₃N₂O₅ (M+H)⁺: 323. Found: 323; (S)-Enantiomer: LRMS ESI calculated for C₁₆H₂₃N₂O₅ (M+H)⁺: 323. Found: 323.

Part III—Synthesis of (S)-methyl 2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate

A stirred solution of (S)-methyl 2-(6-((tert-butoxycarbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate (20 mg, 0.062 mmol), 3-(trifluoromethyl)benzene-1-sulfonyl chloride (12.88 μL, 0.081 mmol) in THF (310 μL) and pyridine (310 μL) was heated to 60° C. overnight. The mixture was cooled and partitioned between ethyl acetate and saturated NaHCO₃. The organic layer was washed with brine, dried (MgSO₄), and concentrated. The residue was dissolved in DMSO (1 mL), filtered, and purified by reverse phase chromatography. LRMS ESI calculated for C₁₉H₁₈F₃N₂O₇S (M+H-tBu)⁺: 475. Found: 475. ¹H NMR: (300 MHz, CDCl₃): δ 9.29 (1H, s), 8.08 (2H, m), 8.01 (2H, m), 7.84 (1H, t, J=6.98 Hz), 7.03 (1H, m), 6.68 (1H, d, J=9.07 Hz), 4.44 (1H, m), 3.78 (1H, m), 3.60 (3H, s), 3.37 (1H, m), 2.80 (1H, m), 2.61 (1H, m), 2.48 (9H, m).

Example 30 Preparation of additional carbamates of (S)-methyl (benzoxazin-2-yl)acetates

The compounds in Table 10 were prepared based on the experimental procedures described in Example 29, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 10 Ex. Observed No. Structure Name m/z 30A

(S)-methyl 2-(6-((tert- butoxycarbonyl)amino)-4-((3-chloro-4- fluorophenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)acetate 533 (M + NH₄)⁺ 30B

(S)-methyl 2-(6-((tert- butoxycarbonyl)amino)-4-((4-fluoro-3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-2- yl)acetate 566 (M + NH₄)⁺ 30C

(S)-methyl 2-(6-((tert- butoxycarbonyl)amino)-4-((4-fluoro-3- methoxyphenyl)sulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-2-yl)acetate 528 (M + NH₄)⁺ 30D

(R)-methyl 2-(6-((tert- butoxycarbonyl)amino)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-2- yl)acetate 475.1 (M-tBu + H)⁺ 30E

(S)-methyl 2-(4-((4-fluoro-3- (trifluoromethyl)phenyl)sulfonyl)-6- ((((1,1,1-trifluoro-2-methylpropan-2- yl)oxy)carbonyl)amino)-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)acetate 624.7 (M + Na)⁺

Example 31 Synthesis of [(S)-6-tert-butoxycarbonylamino-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl]-acetic acid (31)

To a stirred solution of [(S)-6-tert-butoxycarbonylamino-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl]-acetic acid methyl ester (1.5 g, 2.9 mmol) in 1,2-dichloroethane was added trimethyltin hydroxide (2.61 g, 14.5 mmol). The mixture was heated at 90° C. for 4 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. The organic layer was washed with 0.1N HCl and brine, dried and concentrated. The residue was purified by flash column chromatography to afford the title compound. LRMS (ESI) calculated for C₂₀H₂₅F₂N₄O₇S (M+H)⁺: 503. Found: 503.5.

Example 32 Preparation of additional carbamates of (S)-(benzoxazin-2-yl)acetates

The compounds in Table 11 below were prepared based on the experimental procedures described in Example 31 and elsewhere in the detailed description, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 11 Ex. Observed No. Structure Name m/z 32A

(S)-2-(6-((tert-butoxycarbonyl)amino)-4- ((4-fluoro-3-methoxyphenyl)sulfonyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-2- yl)acetic acid 514 (M + NH₄)⁺ 32B

(S)-2-(6-((tert-butoxycarbonyl)amino)-4- ((4-fluoro-3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-2- yl)acetic acid 552 (M + NH₄)⁺ 32C

(S)-2-(6-((tert-butoxycarbonyl)amino)-4- ((3-chloro-4-fluorophenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-2- yl)acetic acid 518 (M + NH₄)⁺ 32D

(S)-2-(6-((tert-butoxycarbonyl)amino)-4- ((3-(trifluoromethyl)phenyl)sulfonyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-2- yl)acetic acid 461.0 (M + H-tBu)⁺ 32E

(S)-2-(6-((tert-butoxycarbonyl)amino)-4- ((4-fluorophenyl)sulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-2-yl)acetic acid 411.1 (M-tBu + H)⁺ 32F

(S)-2-(4-((4-fluorophenyl)sulfonyl)-6- (((neopentyloxy)carbonyl)amino)-3,4- dihydro-2H-benzo[b][1,4]oxazin-2- yl)acetic acid 481.1 (M + H)⁺ 32G

(S)-2-(6-((tert-butoxycarbonyl)amino)-4- ((3-chlorophenyl)sulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-2-yl)acetic acid 427.0 (M + H-tBu)⁺ 32H

(S)-2-(4-((4-fluoro-3- (trifluoromethyl)phenyl)sulfonyl)-6- ((((1,1,1-trifluoro-2-methylpropan-2- yl)oxy)carbonyl)amino)-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)acetic acid 610.8 (M + Na)⁺

Example 33 Synthesis of (R)-6-((tert-butoxycarbonyl)amino)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic acid (33)

A mixture of (R)-tert-butyl (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (500 mg, 1.057 mmol), N-methylmorpholine N-oxide (1.24 g, 10.57 mmol), tetrapropylammonium perruthenate (37.2 mg, 0.106 mmol) and acetonitrile (4.2 mL) was stirred at room temperature for fifteen minutes. The mixture was partitioned between dichloromethane and washed with pH 3 buffer. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried (MgSO₄) and concentrated. The residue was purified by reverse phase HPLC using a solvent system of MeCN/water modified with 0.1% TFA. The product-containing fractions were diluted with ethyl acetate and washed with pH 3 buffer and saturated aqueous sodium chloride. The organic phase was dried (MgSO₄) and concentrated to give (R)-6-((tert-butoxycarbonyl)amino)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic acid as a white foam. MS ESI calculated for C₂₀H₂₄ClFN₃O₇S (M+NH₄)⁺: 504. Found: 504. ¹H NMR (600 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.09 (d, J=8.0 Hz, 1H), 8.03 (s, 1H), 8.02 (s, 1H), 7.99 (s, 1H), 7.79 (t, J=7.9 Hz, 1H), 6.98 (d, J=8.8 Hz, 1H), 6.64 (d, J=8.9 Hz, 1H), 4.48 (dd, J=14.0, 2.3 Hz, 1H), 3.72 (d, J=8.2 Hz, 1H), 3.25 (dd, J=14.1, 9.7 Hz, 1H), 2.39 (dd, J=15.9, 5.6 Hz, 1H), 2.32 (dd, J=16.0, 7.7 Hz, 1H), 1.44 (s, 9H).

Example 34 Preparation of additional carbamates of (R)-6-((tert-butoxycarbonyl)amino)-4-((substituted aryl or heteroaryl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic acids

The compounds in Table 12 below were prepared based on the experimental procedures described in Example 33 and elsewhere in the detailed description, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 12 Ex. Observed No. Structure Name m/z 34A

(R)-6-((tert-butoxycarbonyl)amino)-4-((4- fluorophenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazine-2-carboxylic acid 470 (M + NH₄)⁺ 34B

(R)-6-((tert-butoxycarbonyl)amino)-4-((4- fluoro-3-methoxyphenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazine-2- carboxylic acid 500.0 (M + NH₄)⁺ 34C

(R)-4-((4-fluoro-3- (trifluoromethyl)phenyl)sulfonyl)-6- ((((1,1,1-trifluoro-2-methylpropan-2- yl)oxy)carbonyl)amino)-3,4-dihydro-2H- benzo[b][1,4]oxazine-2-carboxylic acid 592.0 (M + NH₄)⁺ 34D

(R)-6-((tert-butoxycarbonyl)amino)-4-((1- (difluoromethyl)-3-methyl-1H-pyrazol-4- yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazine-2-carboxylic acid 511.0 (M + Na)⁺ 34E

(R)-6-((tert-butoxycarbonyl)amino)-4-((4- fluoro-3-(trifluoromethyl)phenyl)sulfonyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazine-2- carboxylic acid 542.9 (M + Na)⁺

Example 35 Synthesis of [(S)-2-(2-azetidin-1-yl-2-oxo-ethyl)-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic acid tert-butyl ester (35)

To a stirred solution of [(S)-6-tert-butoxycarbonylamino-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl]-acetic acid (0.9 g, 1.8 mmol), azetidine hydrochloride salt (0.21 g, 2.34 mmol) and triethyl amine (1.5 mL, 10.8 mmol) in dichloromethane (92 mL) was added (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1.03 g, 2.34 mmol). The mixture was heated at 40° C. for an hour, then diluted with ethyl acetate and washed with 1N NaOH, brine, 0.1N HCl and water. The organic layer was then dried and concentrated. The residue was purified by silica gel chromatography to provide [(S)-2-(2-azetidin-1-yl-2-oxo-ethyl)-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic acid tert-butyl ester. LC/MC (ESI) m/z 542.5.

Example 36 Synthesis of [(S)-2-(2-azetidin-1-yl-2-oxo-ethyl)-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic acid 1,2,2-trimethyl-propyl ester (36)

The title compound was prepared according to the procedures described below.

Part I—Synthesis of 2-[(S)-6-amino-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl]-1-azetidin-1-yl-ethanone, hydrochloride salt

[(S)-2-(2-Azetidin-1-yl-2-oxo-ethyl)-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic acid tert-butyl ester was treated with 4N HCl-dioxane (5 mL) and the mixture was stirred at room temperature for one hour, then concentrated. The residual white solid was washed with ethyl acetate and dried to provide the title compound. LC/MC (ESI) m/z 442.4.

Part II—Synthesis of [(S)-2-(2-azetidin-1-yl-2-oxo-ethyl)-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic acid 1,2,2-trimethyl-propyl ester

A mixture of 2-[(S)-6-amino-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl]-1-azetidin-1-yl-ethanone, hydrochloride salt (44 mg, 0.1 mmol) and triethyl amine in anhydrous dichloromethane (0.5 mL) was added to a stirred solution of triphosgene (6 mg, 0.03 mmol) in dichloromethane (0.1 mL) at 0° C. The resulting solution was allowed to stir at room temperature for fifteen minutes and then 3,3-dimethyl-butan-2-ol (15 mg, 0.15 mmol) was added, and the resulting mixture was stirred continuously for an hour. The organic phase was concentrated and the residue was purified by HPLC to afford [(S)-2-(2-azetidin-1-yl-2-oxo-ethyl)-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic acid 1,2,2-trimethyl-propyl ester.

Example 37 Preparation of additional amides from (S)-(benzoxazin-2-yl)acetates

The compounds in Table 13 below were prepared based on the experimental procedures described in Examples 35 and 36 and elsewhere in the detailed description, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 13 Ex. Observed No. Structure Name m/z 37A

(S)-tert-butyl (2-(2- amino-2-oxoethyl)-4- ((4-fluorophenyl)sulfonyl)- 3,4-dihydro- 2H-benzo[b][1,4]oxazin-6- yl)carbamate 483 (M + H₂O)⁺ 37B

(S)-tert-butyl (2-(2- amino-2-oxoethyl)-4- ((3-(trifluoromethyl) phenyl)sulfonyl)- 3,4-dihydro-2H-benzo [b][1,4]oxazin-6- yl)carbamate 460.2 (M + H-tBu)⁺ 37C

(S)-tert-butyl (4-((4- fluorophenyl) sulfonyl)-2-(2- (methylamino)-2-oxoethyl)- 3,4-dihydro- 2H-benzo[b][1,4]oxazin-6- yl)carbamate 478 (M + H)⁺ 37D

(S)-tert-butyl (2-(2- (methylamino)-2- oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo [b][1,4]oxazin-6- yl)carbamate 552 (M + Na)⁺ 37E

(S)-tert-butyl (2-(2- (dimethylamino)-2- oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo [b][1,4]oxazin-6- yl)carbamate 544 (M + H)⁺ 37F

tert-butyl (2-(2- (dimethylamino)-2- oxoethyl)-4-((4- fluorophenyl)sulfonyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 492 (M − H)⁻ 37G

(R)-tert-butyl (4-((3-chloro-4- fluorophenyl) sulfonyl)-2-(2- (methylamino)-2-oxoethyl)- 3,4-dihydro- 2H-benzo[b][1,4] oxazin-6-yl)carbamate 514 (M + H)⁺ 37H

(S)-tert-butyl (4-((3-chloro-4- fluorophenyl) sulfonyl)-2-(2- (methylamino)-2-oxoethyl)- 3,4-dihydro- 2H-benzo[b][1,4] oxazin-6-yl)carbamate 514 (M + H)⁺ 37i

1,1,1-trifluoro-2- methylpropan-2-yl (4- ((3-chloro-4-fluorophenyl) sulfonyl)-2-(2- (methylamino)-2- oxoethyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6- yl)carbamate 568 (M + H)⁺ 37J

(R)-tert-butyl (2-(2- (oxazolidin-3-yl)-2- oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 516 (M-tBu + H)⁺ 37K

(S)-tert-butyl (2-(2- ((cyclobutylmethyl) amino)-2-oxoethyl)- 4-((3-(trifluoromethyl) phenyl)sulfonyl)- 3,4-dihydro-2H-benzo [b][1,4]oxazin-6- yl)carbamate 528 (M-tBu + H)⁺ 37L

(S)-tert-butyl (2- (2-oxo-2-((3,3,3- trifluoropropyl)amino) ethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4] oxazin-6- yl)carbamate 556 (M-tBu + H)⁺ 37M

(S)-tert-butyl (2-(2- (isobutylamino)-2- oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 516 (M-tBu + H)⁺ 37N

(S)-tert-butyl (2-(2- (((1H-pyrazol-4- yl)methyl)amino)-2- oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 596 (M + H)⁺ 37o

(S)-tert-butyl (2-(2- (((1-methyl-1H- pyrazol-4-yl)methyl) amino)-2-oxoethyl)- 4-((3-(trifluoromethyl) phenyl)sulfonyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 610 (M + H)⁺ 37P

(S)-tert-butyl (2-(2- (((1H-pyrazol-3- yl)methyl)amino)-2- oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 596 (M + H)⁺ 37Q

(S)-tert-butyl (2-(2- (((1-isopropyl-1H- pyrazol-4-yl)methyl) amino)-2-oxoethyl)- 4-((3-(trifluoromethyl) phenyl)sulfonyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 638 (M + H)⁺ 37R

(S)-tert-butyl (2-(2- oxo-2-((pyrazolo[1,5- a]pyridin-3-ylmethyl) amino)ethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 646 (M + H)⁺ 37S

(S)-tert-butyl (2- (2-(((1-ethyl-1H- pyrazol-3-yl)methyl) amino)-2-oxoethyl)- 4-((3-(trifluoromethyl) phenyl)sulfonyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 624 (M + H)⁺ 37T

(S)-tert-butyl (2-(2- (1-methylpyrrolo[3,4- c]pyrazol-5(1H,4H,6H)- yl)-2-oxoethyl)- 4-((3-(trifluoromethyl) phenyl)sulfonyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 622 (M + H)⁺ 37U

(S)-tert-butyl (2-(2- (((1-methyl-1H- pyrazol-3-yl)methyl) amino)-2-oxoethyl)- 4-((3-(trifluoromethyl) phenyl)sulfonyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 610 (M + H)⁺ 37V

(S)-tert-butyl (2- (2-(((1-ethyl-1H- pyrazol-4-yl)methyl) amino)-2-oxoethyl)- 4-((3-(trifluoromethyl) phenyl)sulfonyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 624 (M + H)⁺ 37W

(S)-tert-butyl (2-(2- (((1-ethyl-5-methyl- 1H-pyrazol-4-yl) methyl)amino)-2- oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 638 (M + H)⁺ 37X

(S)-tert-butyl (2-(2- (((1,5-dimethyl-1H- pyrazol-4-yl)methyl) amino)-2-oxoethyl)- 4-((3-(trifluoromethyl) phenyl)sulfonyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 624 (M + H)⁺ 37Y

(S)-tert-butyl (2-(2- (((1-benzyl-1H- pyrazol-4-yl)methyl) amino)-2-oxoethyl)- 4-((3-(trifluoromethyl) phenyl)sulfonyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 686 (M + H)⁺ 37Z

(S)-3-(2-(6-((tert- butoxycarbonyl) amino)-4-((3- (trifluoromethyl) phenyl)sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-2- yl)acetamido)propanoic acid 37AA

(S)-methyl 3-(2-(6-((tert- butoxycarbonyl) amino)-4-((3- (trifluoromethyl) phenyl)sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-2- yl)acetamido) propanoate 546 (M-tBu + H)⁺ 37AB

(S)-tert-butyl (2-(2-oxo-2-((4- (trifluoromethyl)benzyl) amino)ethyl)-4- ((3-(trifluoromethyl) phenyl)sulfonyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 618 (M-tBu + H)⁺ 37AC

(S)-tert-butyl (2-(2- (benzylamino)-2- oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 550 (M-tBu + H)⁺ 37AD

(S)-tert-butyl (2-(2- ((cyclopropylmethyl) amino)-2- oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 514 (M-tBu + H)⁺ 37AE

(S)-tert-butyl (2-(2-oxo-2- (propylamino) ethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 502 (M-tBu + H)⁺ 37AF

(S)-tert-butyl (2-(2-(ethylamino)-2- oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 488 (M-tBu + H)⁺ 37AG

(S)-tert-butyl (2-(2- (oxazolidin-3-yl)-2- oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 516 (M-tBu + H)⁺ 37AH

(S)-neopentyl (2-(2- (methylamino)-2- oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 544 (M-tBu + H)⁺ 37Ai

(S)-tert-butyl (2-(2- (((2H-tetrazol-5- yl)methyl)amino)- 2-oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 542 (M-tBu + H)⁺ 37AJ

(S)-tert-butyl (2-(2-((2- hydroxyethyl)amino)- 2-oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 560 (M + H)⁺ 37AK

(S)-tert-butyl (2-(2- (tert-butylamino)-2- oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 516 (M-tBu + H)⁺ 37AL

tert-butyl ((2S)-2-(2- (2-methylazetidin-1- yl)-2-oxoethyl)-4-((3- (trifluoromethyl) phenyl)sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 570 (M + H)⁺ 37AM

(S)-tert-butyl (2-(2- (3-cyanoazetidin-1- yl)-2-oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 581 (M + H)⁺ 37AN

(S)-tert-butyl (2-(2- (3-methoxyazetidin- 1-yl)-2-oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 586 (M + H)⁺ 37Ao

(S)-tert-butyl (2-(2- (azetidin-1-yl)-2- oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 556 (M + H)⁺ 37AP

(S)-tert-butyl (2-(2- (azetidin-1-yl)-2- oxoethyl)-4-((4- fluorophenyl)sulfonyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 506.1 (M + H)⁺ 39AQ

(S)-tert-butyl (2-(2- (3-methylazetidin-1- yl)-2-oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 570 (M + H)⁺ 37AR

(S)-neopentyl (2-(2- (azetidin-1-yl)-2- oxoethyl)-4-((1- (difluoromethyl)-3- methyl-1H-pyrazol- 4-yl)sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 556.3 (M + H)⁺

Example 38 Preparation of amides from (R)-6-((substituted-alkoxycarbonyl)amino)-4-((substituted aryl or heteroaryl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic acids

The compounds in Table 14 below were prepared based on the experimental procedures described in Examples 33, 34 and 36 and elsewhere in the detailed description, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 14 Ex. Observed No. Structure Name m/z 38A

(R)-tert-butyl (2-carbamoyl-4-((4-fluoro-3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 537.0 (M + NH₄)⁺ 38B

(R)-1,1,1-trifluoro-2-methylpropan-2-yl (2- carbamoyl-4-((4-fluoro-3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 595.9 (M + Na)⁺ 38C

(R)-tert-butyl (2-carbamoyl-4-((4-fluoro-3- methoxyphenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 499.0 (M + NH₄)⁺ 38D

(R)-methyl 3-(6-((tert- butoxycarbonyl)amino)-4-((3-chloro-4- fluorophenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazine-2- carboxamido)propanoate 573 (M + H)⁺ 38E

(R)-tert-butyl (2-carbamoyl-4-((1- (difluoromethyl)-3-methyl-1H-pyrazol-4- yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 505.0 (M + Na)⁺ 38F

(R)-tert-butyl (4-((1-(difluoromethyl)-3- methyl-1H-pyrazol-4-yl)sulfonyl)-2- (dimethylcarbamoyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 538.2 (M + Na)⁺ 38G

(R)-3-(6-((tert-butoxycarbonyl)amino)-4- ((3-chloro-4-fluorophenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazine-2- carboxamido)propanoic acid 575 (M + NH₄)⁺

Example 39 Synthesis of tert-butyl (2-(2-cyanopropan-2-yl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (39)

Step 1—Preparation of N-(3-cyano-3-methyl-2-oxobutyl)-4-fluoro-N-(2-fluoro-5-nitrophenyl)benzenesulfonamide

To a stirred solution of 4-fluoro-N-(2-fluoro-5-nitrophenyl)benzenesulfonamide (2 g, 6.36 mmol) in DMF (25 mL) was added NaH (0.382 g, 9.55 mmol) in one portion at 0° C. After one hour, a solution of 4-bromo-2,2-dimethyl-3-oxobutanenitrile (2.419 g, 12.73 mmol) in DMF (5 mL) was added dropwise. The mixture was stirred at 0° C. for an additional two hours. The mixture was diluted with water (200 mL) and extracted with three times with ethyl acetate. The combined organic layers were washed with brine, dried (Na₂SO₄) and evaporated to dryness. The residue was cooled and triturated with petroleum ether:ethyl acetate (1:1, 20 mL). The solid was filtered, washed twice with cold EtOAc (5 mL each) and dried to afford the title compound. LCMS (ESI): calculated for C₁₈H₁₅F₂N₃O₅S (M+H)⁺: 424. found: 424.

Step 2—Preparation of N-(3-cyano-2-hydroxy-3-methylbutyl)-4-fluoro-N-(2-fluoro-5-nitrophenyl)benzenesulfonamide

To a stirred solution of N-(3-cyano-3-methyl-2-oxobutyl)-4-fluoro-N-(2-fluoro-5-nitrophenyl)benzenesulfonamide (100 mg, 0.236 mmol) in EtOH (5 mL) was added sodium borohydride (89 mg, 2.362 mmol) in one portion at room temperature. The mixture was stirred at room temperature for two hours. The mixture was diluted with water (100 mL) and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated. The residue was purified by prep-TLC eluting with petroleum ether:ethyl acetate (2:1) to afford the title compound as a yellow oil. LCMS (ESI): calculated for C₁₈H₁₇F₂N₃O₅S (M+H)⁺: 426. found: 426.

Step 3—Preparation of 2-(4-((4-fluorophenyl)sulfonyl)-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanenitrile

To a stirred solution of N-(3-cyano-2-hydroxy-3-methylbutyl)-4-fluoro-N-(2-fluoro-5-nitrophenyl)benzenesulfonamide (1.88 g, 4.42 mmol) in DMF (5 mL) was added K₂CO₃ (1.83 g, 13.26 mmol) in one portion at room temperature. The mixture was heated at 80° C. for 1 h. The mixture was diluted with water (150 mL) and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated. The residue was purified by prep-TLC eluting with petroleum ether:ethyl acetate (2:1) to afford the title compound as a yellow oil. LCMS (ESI): calculated for C₁₈H₁₆FN₃O₅S (M+H)⁺: 406. found: 406.

Step 4—Preparation of tert-butyl (2-(2-cyanopropan-2-yl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of 2-(4-((4-fluorophenyl)sulfonyl)-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanenitrile (100 mg, 0.247 mmol) in ethyl acetate (10 mL) was added di-tert-butyl dicarbonate (0.086 mL, 0.370 mmol) and 10% Pd/C (105 mg, 0.987 mmol) in one portion at room temperature under nitrogen. The atmosphere was purged and exchanged with one atmosphere of hydrogen, and stirred at 30° C. for four hours. The mixture was filtered through CELITE, and the filtrate was concentrated. The residue was purified by prep-HPLC and lyophilized under reduced pressure to afford the title compound as a white solid. LCMS (ESI): calculated for C₂₃H₂₆FN₃O₅S (M+H)⁺: 476. found: 476. ¹H-NMR (400 MHz, CDCl₃) δ 7.60-7.77 (m, 3H), 7.24 (s, 1H), 7.16 (t, J=8.42 Hz, 2H), 6.82 (d, J=8.62 Hz, 1H), 4.44 (d, J=14.10 Hz, 1H), 3.23 (dd, J=13.90, 10.76 Hz, 1H), 3.07 (d, J=9.00 Hz, 1H), 1.52 (s, 9H), 1.38 (s, 3H), 1.35 (s, 3H).

Example 40 Synthesis of (R and S) 2-(4-((4-fluorophenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanoic acid (40)

Step 1—Preparation of tert-butyl (4-((4-fluorophenyl)sulfonyl)-2-(2-methyl-1-oxopropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a stirred solution of tert-butyl (2-(2-cyanopropan-2-yl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (1.4 g, 2.94 mmol) in anhydrous toluene (25 mL) at −78° C. was added dropwise diisopropylaluminum hydride (8.83 mL, 8.83 mmol). The mixture was stirred at −78° C. for an additional three hours. The mixture was quenched by MeOH at −78° C. and allowed to warm up to room temperature, and then 50 mL of water and 30 mL 1M aqueous HCl solution were added (note that on larger scales, the DIBAL reduction should be quenched by the addition of saturated aqueous Rochelle's salt). After being stirred at ambient temperature for 10 min, the resulting solution was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated. The crude product of the title compound was used directly without further purification. LCMS (ESI) calculated for C₂₃H₂₇FN₂O₆S (M+H)⁺: 479. found: 479.

Step 2—Preparation of 2-(6-((tert-butoxycarbonyl)amino)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanoic acid

To a solution of tert-butyl (4-((4-fluorophenyl)sulfonyl)-2-(2-methyl-1-oxopropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (1.2 g, 2.508 mmol) in THF (8 mL) and water (2 mL) was added sulfamic acid (1.461 g, 15.05 mmol) and sodium chlorite (0.249 g, 2.76 mmol) in one portion at 0° C. The mixture was stirred at 0° C. for 10 min, followed by the addition of potassium dihydrogen phosphate (4.10 g, 30.1 mmol). The mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with water (80 mL) and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated. The title compound was used directly without purification. LCMS (ESI) calculated for C₂₃H₂₇FN₂O₇S (M+H)⁺: 495. found: 495.

Step 3—Preparation of methyl 2-(6-amino-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanoate

To a stirred solution of 2-((6-((tert-butoxycarbonyl)amino)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanoic acid (1 g, 2.022 mmol) in methanol (10 mL) was added a 4M solution of hydrochloric acid in methanol (30 mL, 120 mmol) at room temperature. The mixture was heated at 90° C. overnight. The mixture was concentrated, and the residue was purified by silica gel chromatography eluting with petroleum ether:ethyl acetate (3:1) to afford the title compound as a yellow oil. LCMS (ESI) calculated for C₁₉H₂₁FN₂O₅S (M+H)⁺: 409. found: 409.

Step 4—Preparation of methyl 2-(4-((4-fluorophenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanoate

To a solution of methyl 2-(6-amino-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanoate (600 mg, 1.469 mmol) in DMSO (5 mL) was added 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (424 mg, 1.91 mmol) in one portion. The mixture was heated at 80° C. overnight, diluted with water (100 mL) and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated. The residue was purified by silica gel chromatography eluting with petroleum ether:ethyl acetate (3:1) to afford the title compound as a yellow oil. LCMS (ESI) calculated for C₂₄H₂₆F₄N₂O₇S (M+H)⁺: 563. found: 563.

Step 5—Preparation of 2-(6-amino-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanoic acid

To a solution of methyl 2-(4-((4-fluorophenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanoate (110 mg, 0.196 mmol) in THF (2 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (46.8 mg, 1.96 mmol) in one portion. The mixture was stirred at 25° C. overnight. The mixture was diluted with water (10 mL), and acidified with dilute HCl to pH=2. The mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, (Na₂SO₄) and evaporated to dryness. The residue was purified by prep-TLC eluting with petroleum ether:ethyl acetate (1:1) to afford the title compound as a yellow oil. LCMS (ESI) calculated for C₁₈H₁₉FN₂O₅S (M+H)⁺: 395. found: 395.

Step 6—Preparation of 2-(4-((4-fluorophenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanoic acid

To a solution of 2-(6-amino-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanoic acid (80 mg, 0.203 mmol) in DMSO (1 mL) was added 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (54.1 mg, 0.243 mmol) in one portion. The mixture was stirred at 80° C. for four hours. The mixture was diluted with water (30 mL) and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated. The residue was purified by prep-HPLC to afford desired compound as a white solid. LCMS (ESI) calculated for C₂₃H₂₄F₄N₂O₇S (M+H)⁺: 549. found: 549. ¹HNMR (400 MHz, CDCl3) δ 7.78 (1H, br. s.), 7.71 (2H, dd, J=8.53, 5.02 Hz), 7.24 (1H, d, J=7.53 Hz), 7.14 (2H, t, J=8.53 Hz), 6.81 (1H, d, J=9.03 Hz), 6.63-6.77 (1H, m), 4.36-4.45 (1H, m), 3.44 (1H, d, J=9.03 Hz), 3.18 (1H, dd, J=14.05, 10.54 Hz), 1.77 (6H, s), 1.25 (3H, s), 1.20 (3H, s)

Example 41 Synthesis of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((4-fluorophenyl)sulfonyl)-2-(2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (41)

Step 1—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl (4-((4-fluorophenyl)sulfonyl)-2-(1-hydrazinyl-2-methyl-1-oxopropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl) carbamate

To a stirred solution at room temperature of 2-(4-((4-fluorophenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanoic acid (55 mg, 0.100 mmol) in THF (2 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (38.4 mg, 0.201 mmol), N-hydroxybenzotriazole (23 mg, 0.15 mmol) and triethylamine (0.042 mL, 0.30 mmol) in one portion. After the mixture was stirred for an hour, hydrazine (9.44 μL, 0.301 mmol) solution in DMF (0.1 mL) was added to the mixture dropwise. The reaction mixture was stirred at room temperature for an additional hour. The mixture was diluted with water (30 mL) and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (Na₂SO₄) and evaporated to dryness. The residue was purified by prep-TLC eluting with petroleum ether:ethyl acetate (1:1) to afford the title compound as a colorless oil. LCMS (ESI) calculated for C₂₃H₂₆F₄N₄O₆S (M+H)⁺: 563. found: 563.

Step 2—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl (4-((4-fluorophenyl)sulfonyl)-2-(2-methyl-1-(2-(methylcarbamoyl)hydrazinyl)-1-oxopropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a stirred solution at room temperature of 1,1,1-trifluoro-2-methylpropan-2-yl (4-((4-fluorophenyl)sulfonyl)-2-(1-hydrazinyl-2-methyl-1-oxopropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (50 mg, 0.089 mmol) in EtOH (2 mL) was added 4-nitrophenyl methylcarbamate (52.3 mg, 0.267 mmol) in one portion. The mixture was stirred at 100° C. overnight. The mixture was concentrated and the residue was purified by prep-TLC eluting with dichloromethane:methanol (20:1) to afford the title compound as a colorless oil. LCMS (ESI) calculated for C₂₅H₂₉F₄N₅O₇S (M+H)⁺: 620. found: 620.

Step 3—Preparation of 3-(2-(6-amino-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propan-2-yl)-4-methyl-1H-1,2,4-triazol-5(4H)-one

To a solution of 1,1,1-trifluoro-2-methylpropan-2-yl (4-((4-fluorophenyl)sulfonyl)-2-(1-hydrazinyl-2-methyl-1-oxopropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (15 mg, 0.027 mmol) in water (2 mL) was added K₂CO₃ (18.43 mg, 0.133 mmol) in one portion at room temperature. The mixture was stirred at 110° C. for two days. The mixture was diluted with water (20 mL) and extracted three times with ethyl acetate. The combined organic layers were dried (Na₂SO₄) and concentrated. The title compound was used directly without purification. LCMS (ESI) calculated for C₂₀H₂₂FN₅O₄S (M+H)⁺: 448. found: 448.

Step 4—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl (4-((4-fluorophenyl)sulfonyl)-2-(2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of 3-(2-(6-amino-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propan-2-yl)-4-methyl-1H-1,2,4-triazol-5(4H)-one (12 mg, 0.027 mmol) in DMSO (1 mL) was added 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (6.55 mg, 0.029 mmol) in one portion at room temperature. The mixture was stirred at 80° C. overnight. The mixture was diluted with water (20 mL) and extracted three times with ethyl acetate. The combined organic layers were dried (Na₂SO₄) and concentrated. The residue was purified by prep-HPLC eluting with acetonitrile with 0.75% trifluoroacetic acid in water) to afford the title compound as a white solid. LCMS (ESI) calculated for C₂₅H₂₇F₄N₅O₆S (M+H)⁺: 602. found: 602. ¹H NMR (400 MHz, CDCl₃) δ 9.12 (1H, br. s.), 7.69-7.79 (3H, m), 7.21-7.26 (1H, m), 7.17 (2H, t, J=8.28 Hz), 6.79 (1H, d, J=9.03 Hz), 6.69 (1H, br. s.), 4.43 (1H, d, J=13.05 Hz), 3.44 (1H, d, J=9.03 Hz), 3.32 (3H, s), 2.95 (1H, dd, J=14.56, 10.54 Hz), 1.77 (6H, s), 1.42 (3H, s), 1.40 (3H, s).

Example 42 Synthesis of (S)-tert-butyl (2-(2-oxo-2-(trifluoromethylsulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (42)

A mixture of (S)-2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic acid (500 mg, 0.968 mmol), trifluoromethanesulfonamide (173 mg, 1.162 mmol), 4-N,N-dimethylaminopyridine (142 mg, 1.16 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (371 mg, 1.936 mmol), and dichloromethane (6450 μL) was stirred at room temperature for 16 hours. The mixture was concentrated, dissolved in DMSO, filtered, and purified directly by reverse-phase HPLC using a gradient solvent system of 10-100% MeCN/water modified with 0.1% TFA. The product-containing fractions were collected, diluted with ethyl acetate and washed with pH 3 buffer. The aqueous phase was extracted with ethyl acetate, and then the combined organic layers were washed with saturated aqueous sodium chloride, dried (MgSO4) and concentrated to yield (S)-tert-butyl (2-(2-oxo-2-(trifluoromethylsulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate as a white foam. MS ESI calculated for C₁₉H₁₆F₆N₃O₈S₂ (M-tBu+H)⁺: 592. Found: 592. ¹H NMR (600 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.09 (d, J=8.1 Hz, 1H), 8.03 (s, 1H), 8.02 (s, 1H), 7.99 (s, 1H), 7.79 (t, J=7.9 Hz, 1H), 6.98 (d, J=8.7 Hz, 1H), 6.64 (d, J=8.8 Hz, 1H), 4.48 (dd, J=14.0, 2.3 Hz, 1H), 3.71 (s, 1H), 3.25 (dd, J=14.1, 9.7 Hz, 1H), 2.39 (dd, J=16.0, 5.5 Hz, 1H), 2.32 (dd, J=16.0, 7.7 Hz, 1H), 1.44 (s, 9H).

Example 43 Preparation of Additional Sulfonylamides of Benzoxazines

The compounds in Table 15 below were prepared based on the experimental procedures described in Examples 42 and elsewhere in the detailed description, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 15 Ex. Observed No. Structure Name m/z 43A

(S)-neopentyl (2-(2- (cyclopropanesulfonamido)-2- oxoethyl)-4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin- 6-yl)carbamate 634 (M + H)⁺ 43B

(S)-neopentyl (4-((1- (difluoromethyl)-3-methyl- 1H-pyrazol-4-yl)sulfonyl)-2-(2- oxo-2-(trifluoromethyl- sulfonamido)ethyl)- 3,4-dihydro-2H-benzo[b][1,4] oxazin-6-yl)carbamate 670.2 (M + Na)⁺ 43C

(5)-tert-butyl (2-(2-oxo-2- (thiazole-2-sulfonamido) ethyl)-4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4] oxazin-6-yl)carbamate 663 (M + H)⁺ 43D

(S)-tert-butyl (2-(2-oxo-2- (pyridine-4-sulfonamido)ethyl)- 4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H-benzo [b][1,4]oxazin-6-yl)carbamate 657 (M + H)⁺ 43E

(S)-tert-buty (2-(2-(1,1- dimethylethylsulfonamido)-2- oxoethyl)-4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin- 6-yl)carbamate 580 (M − tBu + H)⁺ 43F

(S)-tert-butyl (2-(2-oxo-2-(5- (trifluoromethyl)pyridine-2- sulfonamido)ethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H-benzo [b][1,4]oxazin-6-yl)carbamate 725 (M + H)⁺ 43G

(S)-neopentyl (4-((4- fluorophenyl)sulfonyl)-2- (2-oxo-2-(trifluoromethyl- sulfonamido)ethyl)-3,4- dihydro-2H-benzo[b][1,4] oxazin-6-yl)carbamate 43H

(S)-tert-butyl (2-(2-oxo-2- (pyridine-2-sulfonamido) ethyl)-4-((3-(trifluoromethyl (phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4] oxazin-6-yl)carbamate 657 (M + H)⁺ 43i

(S)-tert-butyl (2-(2-oxo-2- (pyridine-3-sulfonamido) ethyl)-4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4] oxazin-6-yl)carbamate 657 (M + H)⁺ 43J

(S)-tert-butyl (2-(2-oxo-2-(4- (trifluoromethyl)pyridine-2- sulfonamido)ethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 725 (M + H)⁺ 43K

(S)-tert-butyl (2-(2-oxo-2- (1H-pyrazole-4- sulfonamido)ethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 646 (M + H)⁺ 43L

(S)-tert-butyl (2-(2-(4- methylpyridine-2- sulfonamido)-2-oxoethyl)- 4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b] [1,4]oxazin-6-yl)carbamate 671 (M + H)⁺ 43M

(S)-tert-butyl (2-(2-(2- fluoro-5-methylphenyl- sulfonamido)-2-oxoethyl)-4- ((3-(trifluoromethyl(phenyl) sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 688 (M + H)⁺ 43N

(S)-tert-butyl (2-(2-(2- fluorophenylsulfonamido)- 2-oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 674 (M + H)⁺ 43o

(S)-tert-butyl (2-(2-oxo-2-(2- (trifluoromethyl)phenyl- sulfonamido)ethyl)- 4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H-benzo [b][1,4]oxazin-6-yl)carbamate 724 (M + H)⁺ 43P

(S)-tert-butyl (2-(2-oxo-2-(3- (trifluoromethyl)phenyl- sulfonamido)ethyl)- 4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6- yl)carbamate 724 (M + H)⁺ 43Q

(S)-tert-butyl (2-(2- (3-fluorophenyl- sulfonamido)-2-oxoethyl)- 4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b] [1,4]oxazin-6-yl)carbamate 674 (M + H)⁺ 43R

(S)-tert-butyl (2-(2- (cyclopropane- sulfonamido)-2- oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 564 (M − tBu + H)⁺ 43S

(S)-tert-butyl (2-(2-(4- methylphenyl- sulfonamido)-2- oxoethyl)-4-((3-(trifluoro- methyl)phenyl)sulfonyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin- 6-yl)carbamate 614 (M − tBu + H)⁺ 43T

(S)-tert-butyl (2-(2-(1- methylethylsulfonamido)- 2-oxoethyl)-4-((3- (trifluoromethyl) phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b] [1,4]oxazin-6-yl)carbamate 639 (M + NH₄)⁺ 43U

(S)-tert-butyl (2-(2- (ethylsulfonamido)-2- oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 625 (M + NH₄)⁺ 43V

(S)-tert-butyl (2-(2- (methylsulfonamido)-2- oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6- yl)carbamate 611 (M + NH₄)⁺ 43W

(S-neopentyl (2-(2- (cyclopropane- sulfonamido)-2- oxoethyl)-4-((1- (difluoromethyl)-3- methyl-1H-pyrazol-4- yl)sulfonyl)-3,4- dihydro-2H-benzo [b][1,4]oxazin-6-yl) carbamate 620 (M + H)⁺ 43X

(S)-tert-butyl (2-(2- (cyclopentane- sulfonamido)- 2-oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 648 (M + H)⁺ 43Y

(S)-tert-butyl (2-(2-(2- methylphenyl- sulfonamido)- 2-oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b] [1,4]oxazin-6-yl)carbamate 670 (M + H)⁺ 43Z

(S)-tert-butyl (2-(2-(4- fluorophenyl- sulfonamido)- 2-oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b] [1,4]oxazin-6- yl)carbamate 674 (M + H)⁺ 43AA

(S)-tert-butyl (2-(2-(2,5- dimethylphenyl- sulfonamido)- 2-oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 684 (M + H)⁺ 43AB

(S)-tert-butyl (2-(2-oxo- 2-(4-propylphenyl- sulfonamido)ethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 698 (M + H)⁺ 43AC

(S)-tert-butyl (2-(2-(6- methylpyridine-2- sulfonamido)-2-oxoethyl)- 4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4- dihydro-2H-benzo [b][1,4]oxazin-6- yl)carbamate 671 (M + H)⁺ 43AD

(S)-neopentyl (2-(2- (cyclopropane- sulfonamido)- 2-oxoethyl)-4-((4- fluorophenyl)sulfonyl)- 3,4-dihydro-2H-benzo [b][1,4]oxazin-6-yl) carbamate 584.0 (M + H)⁺

Example 44 Synthesis of (S)-(2-(2-(methoxyamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamic acid (44)

A mixture of (S)-2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic acid (100 mg, 0.194 mmol), O-methylhydroxylamine hydrochloride (19.4 mg, 0.232 mmol), (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (103 mg, 0.271 mmol), DMF (1290 μL), and N,N′-diisopropylethylamine (101 μL, 0.581 mmol) was stirred at room temperature for sixteen hours. The reaction was filtered, and purified directly by mass-directed reverse phase HPLC using a mobile phase of MeCN/water modified with 0.1% TFA to afford (S)-(2-(2-(methoxyamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamic acid as a white solid. MS ESI calculated for C₁₉H₁₉F₃N₃O₇S (M+H)⁺: 490. Found: 490. ¹H NMR (600 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.25 (s, 1H), 8.10-7.94 (m, 4H), 7.82 (t, J=8.0 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 6.66 (d, J=8.9 Hz, 1H), 4.39 (dd, J=14.0, 2.2 Hz, 1H), 3.82 (s, 1H), 3.55 (s, 3H), 3.37 (dd, J=14.0, 9.4 Hz, 1H), 2.35 (dd, J=14.9, 5.6 Hz, 1H), 2.22 (dd, J=15.0, 7.2 Hz, 1H), 1.44 (s, 9H).

Example 45 Preparation of Additional Hydroxamates of Benzoxazines

The compounds in Table 16 below were prepared based on the experimental procedures described in Example 44 and elsewhere in the detailed description, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 16 Ex. Observed No. Structure Name m/z 45A

(S)-tert-butyl (2-(2-oxo-2- ((2-(trifluoromethyl)phenoxy) amino)ethyl)(trifluoromethyl) phenyl)sulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6-yl) carbamate 676 (M + H)⁺ 45B

(S)-tert-butyl (2-(2-oxo-2- ((pyridin-3-ylmethoxy)amino) ethyl)-4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6- yl)carbamate 623 (M + H)⁺ 45C

(S)-tert-butyl (2-(2-oxo-2- (((4-(trifluoromethyl)benzyl) oxy)amino)ethyl)-4- ((3-(trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b] [1,4]oxazin-6- yl)carbamate 690 (M + H)⁺ 45D

(S)-tert-butyl (2-(2-oxo-2- (((3-(trifluoromethyl)benzyl) oxy)amino)ethyl)-4- ((3-(trifluoromethyl) phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4] oxazin-6-yl)carbamate 690 (M + H)⁺ 45E

(S)-tert-butyl (2-(2-((4- fluorophenoxy)amino)-2- oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4] oxazin-6-yl)carbamate 626 (M + H)⁺ 45F

(S)-tert-butyl (2-(2- ((cyclopentyloxy)amino)- 2-oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4] oxazin-6-yl)carbamate 600 (M + H)⁺ 45G

(S)-tert-butyl (2-(2- (ethoxyamino)-2- oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 560 (M + H)⁺ 45H

(S)-tert-butyl (2-(2- ((benzyloxy)amino)-2- oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b] [1,4]oxazin-6-yl)carbamate 622 (M + H)⁺ 45i

(S)-tert-butyl (2-(2-(((4- methylbenzyl)oxy)amino)- 2-oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b] [1,4]oxazin-6-yl)carbamate 636 (M + H)⁺ 45J

(S)-tert-butyl (2-(2- (isopropoxyamino)-2- oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b] [1,4]oxazin-6-yl)carbamate 574 (M + H)⁺ 45K

(S)-tert-butyl (2-(2-oxo-2- (propoxyamino)ethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4] oxazin-6-yl)carbamate 574 (M + H)⁺

Example 46 Synthesis of (R)-tert-butyl (4-((4-fluorophenyl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (46)

The title compound was prepared according to the procedures described below.

Part I—Synthesis of (R)-tert-butyl (4-((4-fluorophenyl)sulfonyl)-2-(hydrazinecarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R)-6-((tert-butoxycarbonyl)amino)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic acid (500 mg, 1.105 mmol) in dichloromethane (20 mL) at room temperature was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (318 mg, 1.66 mmol) and N-hydroxybenzotriazole (254 mg, 1.658 mmol) followed by hydrazine hydrate (0.347 mL, 11.1 mmol) and the mixture was stirred at room temperature for five hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium chloride, dried (Na₂SO₄) and concentrated. The (R)-tert-butyl (4-((4-fluorophenyl)sulfonyl)-2-(hydrazinecarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate was obtained as a brownish solid and used in the next step without further purification. MS ESI calculated for C₂₀H₂₃N₄O₆S (M+H)⁺: 467. Found: 411 (M-tBu).

Part II—Synthesis of (R)-tert-butyl (4-((4-fluorophenyl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R)-tert-butyl (4-((4-fluorophenyl)sulfonyl)-2-(hydrazinecarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (100 mg, 0.214 mmol) in acetonitrile (3 mL) at room temperature was added carbonyl diimidazole (52.1 mg, 0.322 mmol) followed by triethylamine (0.045 mL, 0.322 mmol). The mixture was stirred at room temperature for 4 hours, then concentrated. The residue was dissolved in DMSO, filtered and purified by reverse phase HPLC using a mobile phase of MeCN/water modified with 0.1% TFA to yield (R)-tert-butyl (4-((4-fluorophenyl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate as a white solid. MS ESI calculated for C₂₁H₂₁FN₄O₇S (M+H)⁺: 493. Found: 493. ¹H NMR (500 MHz, DMSO-d6) δ 12.59 (s, 1H), 9.35 (s, 1H), 7.97-7.80 (m, 3H), 7.44 (t, J=8.8 Hz, 2H), 7.15 (d, J=10.3 Hz, 1H), 6.83 (d, J=8.9 Hz, 1H), 4.80 (d, J=5.1 Hz, 1H), 4.39 (dd, J=14.3, 2.9 Hz, 1H), 3.89 (dd, J=14.3, 8.0 Hz, 1H), 1.49 (s, 9H).

Example 47 Preparation of additional 2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) substituted benzoxazines

The compounds in Table 17 below were prepared based on the experimental procedures described in Example 46 and elsewhere in the detailed description, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 17 Ex. Observed No. Structure Name m/z 47A

(R)-1,1,1-trifluoro-2-methylpropan-2-yl (4- ((4-fluorophenyl)sulfonyl)-2-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6-yl)carbamate 547.0 (M + H)⁺ 47B

(R)-tert-butyl (4-((1-(difluoromethyl)-3- methyl-1H-pyrazol-4-yl)sulfonyl)-2-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 473.1 (M − tBu + H)⁺ 47C

(R)-1,1,1-trifluoro-2-methylpropan-2-yl (4- ((1-(difluoromethyl)-3-methyl-1H-pyrazol- 4-yl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 604.9 (M + Na)⁺ 47D

(R)-tert-butyl (4-((3-chloro-4- fluorophenyl)sulfonyl)-2-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6-yl)carbamate 544 (M + NH₄)⁺ 47E

(R)-tert-butyl (4-((4-fluoro-3- (trifluoromethyl)phenyl)sulfonyl)-2-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 578.0 (M + NH₄)⁺ 47F

(S)-tert-butyl (4-((4- fluorophenyl)sulfonyl)-2-((4-methyl-5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) methyl)-3,4-dihydro-2H-benzo[b][1,4] oxazin-6-yl)carbamate 543 (M + Na)⁺ 47G

(S)-tert-butyl (4-((1-(difluoromethyl)-3- methyl-1H-pyrazol-4-yl)sulfonyl)-2-((4- methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol- 2-yl)methyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 579 (M + Na)⁺ 47H

(S)-tert-butyl (2-((4-methyl-5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)methyl)-4- ((3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 593 (M + Na)⁺

Example 48 Synthesis of (R)-tert-butyl (4-((4-fluorophenyl)sulfonyl)-2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (48)

The title compound was prepared according to the procedures described below.

Part I—Synthesis of (R)-tert-butyl (4-((4-fluorophenyl)sulfonyl)-2-(hydrazinecarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R)-6-((tert-butoxycarbonyl)amino)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic acid (400 mg, 0.884 mmol) in dichloromethane (20 mL) at room temperature was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (254 mg, 1.326 mmol) and N-hydroxybenzotriazole (203 mg, 1.326 mmol) followed by hydrazine hydrate (0.28 mL, 8.84 mmol). The mixture was stirred at room temperature for sixteen hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium chloride, dried (Na₂SO₄) and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate/hexane (0˜100%) to give (R)-tert-butyl (4-((4-fluorophenyl)sulfonyl)-2-(hydrazinecarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate as a white solid. MS ESI calculated for C₂₀H₂₃N₄O₆S (M+H)⁺: 467. Found: 411 (M-tBu).

Part II—Synthesis of (R)-tert-butyl (4-((4-fluorophenyl)sulfonyl)-2-(2-(methylcarbamoyl)hydrazinecarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To (R)-tert-butyl (4-((4-fluorophenyl)sulfonyl)-2-(hydrazinecarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (200 mg, 0.429 mmol) in THF (2 mL) at room temperature was added methyl isocyanate (0.032 mL, 0.51 mmol) and the mixture was stirred at room temperature for three hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaHCO₃, and saturated aqueous sodium chloride, dried (Na₂SO₄) and concentrated to afford (R)-tert-butyl (4-((4-fluorophenyl)sulfonyl)-2-(2-(methylcarbamoyl)hydrazinecarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate which was used in the next step without further purification.

Part III—Synthesis of (R)-tert-butyl (4-((4-fluorophenyl)sulfonyl)-2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To (R)-tert-butyl (4-((4-fluorophenyl)sulfonyl)-2-(2-(methylcarbamoyl)hydrazinecarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (200 mg, 0.382 mmol) at room temperature was added 2M NaOH (3 mL, 6.00 mmol) and the mixture was stirred at 100° C. for sixteen hours. The reaction mixture was allowed to cool to room temperature, acidified with 1N HCl (6 mL) and concentrated. The residue was redissolved in DMSO, filtered and purified by reverse phase HPLC using a solvent system of MeCN/water modified with 0.1% trifluoroacetic acid to give (R)-tert-butyl (4-((4-fluorophenyl)sulfonyl)-2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate. MS ESI calculated for C₂₂H₂₄FN₅O₆S (M+H)⁺: 506. Found: 506 and 450 (M-tBu). ¹H NMR (500 MHz, DMSO-d6) δ 11.88 (s, 1H), 9.34 (s, 1H), 7.92-7.82 (m, 3H), 7.43-7.40 (m, 2H), 7.14 (s, 1H), 6.81 (d, J=8.8 Hz, 1H), 4.77 (d, J=6.9 Hz, 1H), 4.50 (d, J=11.7 Hz, 1H), 3.83 (dd, J=13.9, 9.2 Hz, 1H), 1.45 (s, 9H).

Example 49 Synthesis of tert-butyl (2-(cyanomethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (49)

The title compound was prepared according to the procedures described below.

Part I—Synthesis of (R)-tert-butyl (2-(iodomethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a stirred solution of (R)-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl 4-methylbenzenesulfonate (7.7 g, 12 mmol) in acetone (100 mL) was added sodium iodide (7.0 g, 47 mmol). The mixture was heated at 60° C. and stirred overnight. Solvent was evaporated, brine (50 mL) was added, and the mixture was extracted three times with ethyl acetate (50 mL each). The combined organic phases were dried (Na₂SO₄) and concentrated. The residue was purified by column chromatography on silica gel eluting with ethyl acetate/hexanes 1:4 to afford (R)-tert-butyl (2-(iodomethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate as a white solid. LCMS (ESI) calculated for C₂₁H₂₂F₃IN₂NaO₅S (M+Na)⁺: 621.0. Found: 620.9.

Part II—Synthesis of tert-butyl (2-(cyanomethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a stirred solution of (R)-tert-butyl (2-(iodomethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (3.0 g, 5 mmol) in DMF (30 mL) was added sodium cyanide (490 mg, 10 mmol) at room temperature. The reaction was stirred overnight. The mixture was diluted with brine (50 mL) and extracted three times with ethyl acetate (50 mL each). The organic layers were combined, dried (Na₂SO₄) and concentrated. The residue was purified by Prep-HPLC to give a brown solid as a racemate. LCMS (ESI) calculated for C₂₂H₂₂F₃N₃NaO₅S (M+Na)⁺: 520.1. Found: 520.0.

Example 50 Synthesis of tert-butyl (2-(2-hydroxypropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (50)

The title compound was prepared according to the procedures described below.

Part I—Synthesis of tert-butyl (2-(2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a stirred solution of tert-butyl (2-(cyanomethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (1.0 g, 2.0 mmol) in anhydrous toluene (30 mL) was added a 1M solution of diisobutylaluminum hydride (5 mL, 5 mmol) in toluene at −78° C. The mixture was stirred at −78° C. for one hour and then warmed to room temperature. The reaction was stirred for another hour, and quenched with brine (50 mL). The mixture was extracted three times with ethyl acetate (50 mL each). The organic phases were combined, dried (Na₂SO₄), filtered, and concentrated to afford tert-butyl (2-(2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate as a yellow solid. LCMS (ESI) calculated for C₂₂H₂₃F₃N₂NaO₆S (M+Na)⁺: 523.1. Found: 523.0.

Part II—Synthesis of tert-butyl (2-(2-hydroxypropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a stirred solution of tert-butyl (2-(2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (150 mg, 0.3 mmol) in anhydrous THF (10 mL) was added a 3M solution of methyl magnesium bromide (1.0 mL, 3.0 mmol) in THF dropwise at 0° C. The mixture was stirred at 0° C. for an hour, warmed to room temperature and stirred for another hour, then quenched with saturated aqueous ammonium chloride (5 mL). Brine (10 mL) was added and extracted three times with ethyl acetate (20 mL each). The organic layers were combined, dried (Na₂SO₄) and concentrated. The residue was purified by Prep-HPLC to afford the title compound as a white solid. LCMS (ESI): calculated for C₂₃H₃₁F₃N₃O₆S (M+NH₄)⁺: 534.2. Found: 534.0.

Example 51 Synthesis of (S)-tert-butyl (2-(2-amino-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (51)

Cerium chloride (4.6 g, 18.0 mmol) was dried under vacuum at 140° C. for 2 hours before it was cooled to room temperature. Anhydrous THF (140 mL) was added and the suspension was stirred at room temperature for two hours. Then the suspension was cooled to −78° C., and 3M methyl lithium (6.0 mL, 18.0 mmol) in ether was added dropwise. The mixture was stirred at −78° C. for thirty minutes. A solution of tert-butyl (2-(cyanomethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (1.5 g, 3.0 mmol) in THF (15 mL) was added dropwise and the mixture was stirred for another thirty minutes at −78° C. The resulting mixture was warmed to room temperature and stirred for 1.5 hours. Ammonium hydroxide (25-28% in water, 3 mL) was added and the resulting solution was stirred for ten minutes. Brine (40 mL) was added and extracted with ethyl acetate (30 mL×3). The organic layers were combined, dried (Na₂SO₄), concentrated and the residue purified by prep-HPLC (46-76% acetonitrile+0.75%0 trifluoroacetic acid in water) and SFC-HPLC to give two isomers. SFC separation condition: Column: Chiralpak AS-H 250×4.6 mm I.D., Sum Mobile phase: ethanol (0.05% DEA) in CO2 from 5% to 40% Flow rate: 2.35 mL/min Wavelength: 220 nm. (S)-tert-butyl (2-(2-amino-2-methylpropyl)-4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate RT: 5.294 min. LCMS (ESI): calculated for C₂₄H₃₁F₃N₃O₅S (M+H)⁺: 530. Found: 530; and (R)-tert-butyl (2-(2-amino-2-methylpropyl)-4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate RT: 4.789 min. LCMS (ESI): calculated for C₂₄H₃₁F₃N₃O₅S (M+H)⁺: 530. Found: 530.

Example 52 Synthesis of (S)-tert-butyl (2-(2-acetamido-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (52)

To a stirred solution of (S)-tert-butyl (2-(2-amino-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (180 mg, 0.34 mmol) and triethyl amine (0.1 mL, 0.7 mmol) in dichloromethane (5 mL) was added acetic anhydride (71 mg, 0.7 mmol) at room temperature. The mixture was stirred at room temperature overnight. The solvent was evaporated, brine (20 mL) was added and the mixture was extracted with ethyl acetate (50 mL×3). The organic layers were combined, dried (Na₂SO₄) and concentrated. The residue was purified by prep-HPLC (45-75% acetonitrile+0.75‰ trifluoroacetic acid in water) to give (S)-tert-butyl (2-(2-acetamido-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.08 (br s, 1H), 8.04˜7.95 (m, 2H), 7.83˜7.76 (m, 1H), 7.61 (s, 1H), 7.04 (dd, J=2.0, 8.6 Hz, 1H), 6.70 (d, J=8.6 Hz, 1H), 4.28 (dd, J=2.4, 14.4 Hz, 1H), 3.63 (br s, 1H), 3.28˜3.21 (m, 1H), 2.17 (dd, J=2.8, 14.8 Hz, 1H), 1.91 (s, 3H), 1.90˜1.84 (m, 1H), 1.55 (s, 9H), 1.29 (d, J=6.6 Hz, 6H). LCMS (ESI): calculated for C₂₆H₃₃F₃N₃O₆S (M+H)⁺: 572. Found: 572.

Example 53 Preparation of Additional Amides of Benzoxazines

The compounds in Table 18 below were prepared based on the experimental procedures described in Examples 49, 50, 51 and 52 and elsewhere in the detailed description, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 18 Ex. Observed No. Structure Name m/z 53A

(S)-tert-butyl (2-(2-propionamidoethyl)-4- ((3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 558 (M + H)⁺ 53B

tert-butyl ((2S)-2-(2-(2- hydroxypropanamido)ethyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 574 (M + H)⁺ 53C

(S)-tert-butyl (2-(2-(oxetane-3- carboxamido)ethyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 586 (M + H)⁺ 53D

(S)-tert-butyl (2-(2-isobutyramidoethyl)- 4-((3-(trifluoromethyl)phenyl)sulfonyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 572 (M + H)⁺ 53E

(S)-tert-butyl (2-(2-acetamidoethyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 566 (M + Na)⁺ 53F

(S)-tert-butyl (2-(2- (cyclopropanecarboxamido)ethyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 570 (M + H)⁺ 53G

(S)-tert-butyl (4-((4- fluorophenyl)sulfonyl)-2-(2- propionamidoethyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 508 (M + H)⁺ 53H

(S)-tert-butyl (2-(2-acetamidoethyl)-4-((4- fluorophenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 494 (M + H)⁺ 53i

tert-butyl ((2S)-4-((4- fluorophenyl)sulfonyl)-2-(2-(2- hydroxypropanamido)ethyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6-yl)carbamate 524 (M + H)⁺ 53J

(S)-tert-butyl (2-(2- (cyclopropanecarboxamido)ethyl)-4-((4- fluorophenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 520 (M + H)⁺ 53K

(S)-neopentyl (4-((4- fluorophenyl)sulfonyl)-2-(2- propionamidoethyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 522 (M + H)⁺ 53L

(S)-neopentyl (2-(2-acetamidoethyl)-4- ((4-fluorophenyl)sulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6-yl)carbamate 508 (M + H)⁺ 53M

(S)-neopentyl (2-(2- (cyclopropanecarboxamido)ethyl)-4-((4- fluorophenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 533 (M + H)⁺ 53N

(S)-1,1,l-trifluoro-2-methylpropan-2-yl (2-(2-amino-2-methylpropyl)-4-((3- chloro-4-fluorophenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 568 (M + H)⁺ 53o

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-amino-2-methylpropyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 584 (M + H)⁺ 53P

(R)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 624 (M + H)⁺ 53Q

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 624 (M + H)⁺

Example 54 Synthesis of (S)-tert-butyl (2-(2-acetamido-2-methylpropyl)-4-((3-chloro-4-fluorophenyl) sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (54)

The title compound was prepared according to the procedures described below.

Part I—Synthesis of (S)-benzyl 6-((tert-butoxycarbonyl)amino)-2-(2-methoxy-2-oxoethyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate

To a solution of (S)-methyl 2-(6-((tert-butoxycarbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate (0.5 g, 1.6 mmol) and sodium bicarbonate (0.52 g, 6.2 mmol) in dry THF (5 mL) was added benzyl chloroformate (0.53 g, 6.2 mmol) at 0° C. The mixture was stirred at reflux for an hour, poured into ice-water (10 mL), and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (5 mL), dried (Na₂SO₄) and concentrated to afford compound (S)-benzyl 6-((tert-butoxycarbonyl)amino)-2-(2-methoxy-2-oxoethyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.89 (br s, 1H), 7.31˜7.48 (m, 5H), 7.07 (br s, 1H), 6.80 (d, J=8.8 Hz, 1H), 6.37 (br s, 1H), 5.26 (s, 2H), 4.52˜4.64 (m, 1H), 4.21 (dd, J=2.4, 13.2 Hz, 1H), 3.70 (s, 3H), 3.49 (dd, J=7.6, 13.2 Hz, 1H), 2.66˜2.77 (m, 1H), 2.54˜2.64 (m, 1H), 1.50 (s, 9H). LCMS (ESI): calculated for C₂₄H₂₉N₂O₇ (M+H)⁺: 457. Found: 457.

Part II—Synthesis of (S)-benzyl 6-((tert-butoxycarbonyl)amino)-2-(2-hydroxy-2-methylpropyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate

To a solution of (S)-benzyl 6-((tert-butoxycarbonyl)amino)-2-(2-methoxy-2-oxoethyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (0.4 g, 0.88 mmol) in dry THF (5 mL) at 0° C. was added dropwise 3M methyl magnesium bromide (2.9 mL, 8.7 mmol) in THF. The mixture was stirred at room temperature for five hours. The resulting mixture was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were dried (Na₂SO₄) and concentrated to afford (S)-benzyl 6-((tert-butoxycarbonyl)amino)-2-(2-hydroxy-2-methylpropyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.91 (br s, 1H), 7.30˜7.47 (m, 5H), 7.07 (br s, 1H), 6.79 (d, J=8.8 Hz, 1H), 6.35 (br s, 1H), 5.26 (s, 2H), 4.36˜4.49 (m, 1H), 4.18 (dd, J=2.0, 13.6 Hz, 1H), 3.37 (dd, J=8.0, 13.2 Hz, 1H), 2.40 (br s, 1H), 1.80˜1.91 (m, 1H), 1.67 (dd, J=3.2, 14.8 Hz, 1H), 1.50 (s, 9H), 1.31 (d, J=9.6 Hz, 6H). LCMS (ESI): calculated for C₂₅H₃₃N₂O₆ (M+H)⁺: 457. Found: 457.

Part III—Synthesis of (S)-benzyl 2-(2-acetamido-2-methylpropyl)-6-amino-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate

To a solution of compound (S)-benzyl 6-((tert-butoxycarbonyl)amino)-2-(2-hydroxy-2-methylpropyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (0.05 g, 0.11 mmol) in acetonitrile (5 mL) was added dropwise concentrated sulfuric acid (107 mg, 1.1 mmol) at 0° C. The mixture was stirred at room temperature for 5 hours. The resulting mixture was poured into ice-water (3 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (5 mL), dried (Na₂SO₄) and concentrated to afford compound (S)-benzyl 2-(2-acetamido-2-methylpropyl)-6-amino-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate. ¹H NMR (400 MHz, CDCl₃) δ 7.33-7.43 (m, 5H), 6.63 (d, J=8.4 Hz, 1H), 6.37 (dd, J=2.8, 8.8 Hz, 1H), 5.95 (br s, 1H), 5.24 (s, 2H), 4.21 (t, J=8.8 Hz, 1H), 4.05 (dd, J=2.0, 13.2 Hz, 1H), 3.40 (dd, J=8.4, 13.2 Hz, 1H), 1.97˜2.04 (m, 2H), 1.79-1.90 (m, 3H), 1.34 (s, 6H). LCMS (ESI): calculated for C₂₂H₂₈N₃O₄ (M+H)⁺: 398. Found: 398.

Part IV—Synthesis of (S)-benzyl 2-(2-acetamido-2-methylpropyl)-6-((tert-butoxycarbonyl)amino)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate

To a solution of (S)-benzyl 2-(2-acetamido-2-methylpropyl)-6-amino-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (1.2 g, 3 mmol) and sodium bicarbonate (0.5 g, 6 mmol) in methanol (5 mL) was added di-tert-butyl dicarbonate (0.94 g, 4.5 mmol) at 0° C. The mixture was stirred at room temperature for two hours. The resulting mixture was poured into ice-water (10 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (5 mL), dried (Na₂SO₄) and concentrated to afford (S)-benzyl 2-(2-acetamido-2-methylpropyl)-6-((tert-butoxycarbonyl)amino)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate. ¹H NMR (400 MHz, CDCl₃) δ 7.95 (br s, 1H), 7.37-7.44 (m, 5H), 7.11 (br s, 1H), 6.75 (d, J=8.8 Hz, 1H), 6.48 (br s, 1H), 6.14 (br s, 1H), 5.24˜5.30 (m, 2H), 4.27 (t, J=8.4 Hz, 1H), 4.05˜4.09 (d, J=13.6 Hz, 1H), 3.41˜3.46 (dd, J=8.4, 13.6 Hz, 1H), 1.88˜2.06 (m, 5H), 1.52 (s, 9H), 1.43 (s, 6H). LCMS (ESI): calculated for C₂₇H₃₆N₃O₆ (M+H)⁺: 498. Found: 498.

Part V—Synthesis of (S)-tert-butyl (2-(2-acetamido-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution (S)-benzyl 2-(2-acetamido-2-methylpropyl)-6-((tert-butoxycarbonyl)amino)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (1 g, 2 mmol) in ethyl acetate (10 mL) was added 10% Pd/C (200 mg, 10% wt) under nitrogen. The mixture was stirred at room temperature under hydrogen at 1 atmosphere for three hours. The resulting mixture was filtered through a CELITE pad and the filtrate was concentrated to afford (S)-tert-butyl (2-(2-acetamido-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 6.89 (br s, 1H), 6.62 (d, J=8.4 Hz, 1H), 6.41 (d, J=8.0 Hz, 1H), 6.33 (br s, 1H), 6.15 (br s, 1H), 4.19˜4.31 (m, 1H), 3.21˜3.34 (m, 1H), 3.08˜3.19 (m, 1H), 1.89˜1.95 (m, 5H), 1.44 (s, 9H), 1.34 (s, 6H). LCMS (ESI): calculated for C₁₉H₃₀N₃O₄ (M+H)⁺: 364. Found: 364.

Part VI—Synthesis of (S)-tert-butyl (2-(2-acetamido-2-methylpropyl)-4-((3-chloro-4-fluorophenyl) sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-tert-butyl (2-(2-acetamido-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (0.05 g, 0.1 mmol) and pyridine (1 mL) in dry THF (2 mL) was added sulfonyl chloride (0.06 g, 1.1 mmol) at 0° C. The mixture was stirred at reflux for an hour. The resulting mixture was poured into ice-water (10 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (5 mL), dried (Na₂SO₄) and concentrated. The residue was purified by prep-HPLC (45-75% acetonitrile+0.75%0 trifluoroacetic acid in water) to give (S)-tert-butyl (2-(2-acetamido-2-methylpropyl)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.89 (d, J=5.2 Hz, 1H), 7.74 (br s, 1H), 7.61 (br s, 1H), 7.09˜7.25 (m, 2H), 6.71 (d, J=8.8 Hz, 1H), 6.43 (br s, 1H), 5.58 (br s, 1H), 4.13 (d, J=13.6 Hz, 1H), 3.63˜3.80 (m, 1H), 3.20 (dd, J=9.6, 14.0 Hz, 1H), 2.13 (d, J=14.0 Hz, 1H), 1.92 (s, 3H), 1.79 (dd, J=8.4, 14.8 Hz, 1H), 1.52 (s, 9H), 1.34 (d, J=6.8 Hz, 6H). LCMS (ESI): calculated for C₂₅H₃₂ClFN₃O₄S (M+H)⁺: 556. Found: 556.

Example 55 Preparation of Additional Amides of Benzoxazines

The compounds in Table 19 below were prepared based on the experimental procedures described in Example 54 and elsewhere in the detailed description, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 19 Ex. Observed No. Structure Name m/z 55A

(S)-tert-butyl (2-(2-acetamido-2- methylpropyl)-4-((3,4- difluorophenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 540 (M + H)⁺ 55B

(S)-tert-butyl (2-(2-acetamido-2- methylpropyl)-4-((1-(difluoromethyl)-3- methyl-1H-pyrazol-4-yl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 558 (M + H)⁺ 55C

(S)-tert-butyl (2-(2-acetamido-2- methylpropyl)-4-((1-(difluoromethyl)-5- methyl-1H-pyrazol-4-yl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 558 (M + H)⁺ 55D

(S)-tert-butyl (2-(2-acetamido-2- methylpropyl)-4-((4-fluorophenyl)sulfonyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 522 (M + H)⁺ 55E

(R)-tert-butyl (2-(2-acetamido-2- methylpropyl)-4-((4-fluorophenyl)sulfonyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 522 (M + H)⁺

Example 56 Synthesis of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-acetamido-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (56)

A mixture of (S)—N-(1-(6-amino-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropan-2-yl)acetamide (100 mg, 0.21 mmol), 4-nitrophenyl 1,1,1-trifluoro-2-methylpropan-2-yl carbonate (130 mg, 0.44 mmol) and N,N′-diisopropylethylamine (0.2 mL) were stirred at 120° C. for two hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layers were washed with 1N NaOH, brine, (Na₂SO₄) and concentrated. The residue was purified by prep-TLC (petroleum ether:ethyl acetate=1:1) and prep-HPLC to give (S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-acetamido-2-methylpropyl)-4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate. ¹H NMR (400 MHz, CDCl₃) δ 8.08 (br s, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.85 (d, J=7.6 Hz, 2H), 7.60˜7.69 (m, 1H), 7.07 (dd, J=8.8, 2.2 Hz, 1H), 6.71 (d, J=9.2 Hz, 1H), 6.65 (s, 1H), 5.92 (br s, 1H), 4.13˜4.18 (m, 1H), 3.73 (br s, 1H), 3.23 (dd, J=14.0, 9.6 Hz, 1H), 1.95˜2.03 (m, 4H), 1.83˜1.92 (m, 1H), 1.76 (s, 6H), 1.36 (s, 3H), 1.30 (s, 3H). LCMS (ESI): calculated for C₂₆H₃₀F6N₃O₆S (M+H)⁺: 626. Found: 626.

Example 57 Preparation of Additional Amides of Benzoxazines

The compounds in Table 20 below were prepared based on the experimental procedures described in Example 56 and elsewhere in the detailed description, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 20 Ex. Observed No. Structure Name m/z 57A

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-acetamido-2-methylpropyl)-4-((4- fluorophenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 576 (M + H)⁺ 57B

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-acetamido-2-methylpropyl)-4-((3- chloro-4-fluorophenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 610 (M + H)⁺ 57C

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-acetamido-2-methylpropyl)-4-((1- (difluoromethyl)-3-methyl-1H-pyrazol- 4-yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 612 (M + H)⁺ 57D

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((4-fluorophenyl)sulfonyl)-2-(2- methyl-2-(methylsulfonamido)propyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 612 (M + H)⁺ 57E

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-acetamido-2-methylpropyl)-4- ((3,4-difluorophenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 594 (M + H)⁺ 57F

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((3-chloro-4-fluorophenyl)sulfonyl)- 2-(2-methyl-2- (methylsulfonamido)propyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 668 (M + Na)⁺ 57G

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((3,4-difluorophenyl)sulfonyl)-2-(2- methyl-2-(methylsulfonamido)propyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 630 (M + H)⁺ 57H

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-(cyclopropanesulfonamido)-2- methylpropyl)-4-((3,4- difluorophenyl)sulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6-yl)carbamate 678 (M + Na)⁺ 57i

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-methyl-2- (methylsulfonamido)propyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 684 (M + Na)⁺ 57J

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-(cyclopropanesulfonamido)-2- methylpropyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 710 (M + Na)⁺ 57K

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((3-chloro-4-fluorophenyl)sulfonyl)- 2-(2-methyl-2- (methylsulfonamido)propyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 694 (M + Na)⁺ 57L

(S)-1,1,1-trifluoro-2-mrthylpropan-2-yl (2-(2-(cyclopropanrsulfonamido)-2- methylpropyl)-4-((4- fluorophenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 638 (M + H)⁺ 57M

(R)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-(cyclopropanesulfonamido)-2- methylpropyl)-4-((4- fluorophenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 638 (M + H)⁺ 57N

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-methyl-2- (trifluoromethylsulfonamido)propyl)-4- ((3-(trifluoromethyl(phenyl(sulfonyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 716 (M + H)⁺ 57o

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-(2-(dimethylamino)-2- oxoacetamido)-2-methylpropyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 683 (M + H)⁺ 57P

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-acetamido-2-methylpropyl)-4-((4- fluoro-3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- carbamate 644 (M + H)⁺ 57Q

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-acetamido-2-methylpropyl)-4-((3- chloro-1-ethyl-1H-pyrazol-4- yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 611 (M + H)⁺ 57R

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-acetamido-2-methylpropyl)-4-((3- methoxy-1,5-dimethyl-1H-pyrazol-4- yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 606 (M + H)⁺ 57S

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-acetamido-2-methylpropyl)-4-((1- (difluoromethyl)-3-ethoxy-1H-pyrazol-4- yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 642 (M + H)⁺ 57T

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-acetamido-2-methylpropyl)-4-((3- (difluoromethoxy)-1-ethyl-1H-pyrazol-4- yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 642 (M + H)⁺ 57U

2,2,2-trifluoro-1,1-dimethylethyl [(2S)-2- [2-(acetylamino)-2-methylpropyl]-4-{[l- ethyl-3-(2-hydroxyethoxy)-1H-pyrazol-4- yl]sulfonyl}-3,4-dihydro-2H-1,4- benzoxazin-6-yl]carbamate 636 (M + H)⁺

Example 58 Synthesis of tert-butyl (2-(2-hydroxyethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (58)

To a solution of (6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic acid (240 mg, 0.47 mmol) in anhydrous THF (10 mL) was added 1 M solution of borane (4.5 mL, 4.65 mmol) in THF at 0° C. The mixture was stirred at room temperature overnight and quenched with methanol (5 mL). The mixture was concentrated, diluted with water (20 mL), and extracted three times with ethyl acetate (15 mL each). The organic layers were combined (Na₂SO₄) and concentrated. The residue was purified by reverse phase chromatography (water/MeOH=50/50) MPLC to give the title compound. LCMS (ESI) calculated for C₂₂H₂₅F₃N₂NaO₆S (M+Na)⁺: 525.1. Found: 525.1. ¹H NMR (400 MHz, CD₃OD): δ 8.08 (1H, s), 8.04 (2H, d, J=8.8 Hz), 7.96 (1H, d, J=7.6 Hz), 7.75 (1H, t, J=8.0 Hz), 7.03 (1H, dd, J=8.4, 2.0 Hz), 6.72 (1H, d, J=8.4 Hz), 4.47 (1H, dd, J=14.4, 2.0 Hz), 3.63-3.70 (3H, m), 3.24-3.30 (1H, m), 1.74-1.78 (2H, m), 1.55 (9H, s).

Example 59 Synthesis of tert-butyl (2-((1H-imidazol-2-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (59)

Aqueous ammonium hydroxide (25% w/w, 0.15 mL) was added to solution of (6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic acid (145 mg, 0.29 mmol) in methanol (2 mL). Glyoxal (40% (w/w) in water, 0.05 mL) was added dropwise to the above mixture and the reaction was stirred at room temperature for twelve hours. The solvent was removed and the residue was purified by Prep-HPLC to afford the title compound. LCMS (ESI) calculated for C₂₄H₂₆F₃N₄O₅S (M+H)⁺: 539.2. Found: 539.0. ¹H NMR (400 MHz, CD₃OD): δ 8.02-7.94 (4H, m), 7.74 (1H, t, J=7.6 Hz), 7.05-7.01 (3H, m), 6.76 (1H, d, J=8.8 Hz), 4.42 (1H, d, J=14.4 Hz), 3.76-3.74 (1H, m), 3.23 (1H, dd, J=14, 9.6 Hz), 3.03-2.97 (2H, m), 1.54 (9H, s).

Example 60 Synthesis of tert-butyl (2-((1-methyl-1H-imidazol-2-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (60)

To a solution of tert-butyl (2-((1H-imidazol-2-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (30 mg, 0.056 mmol) in DMF (2 mL) was added potassium carbonate (12 mg, 0.084 mmol) and methyl iodide (8 mg, 0.056 mmol) at 0° C. The reaction was stirred at room temperature for twelve hours and then concentrated. The residue was purified by Prep-HPLC to afford the title compound. LCMS (ESI) calculated for C₂₅H₂₈F₃N₄O₅S (M+H)⁺: 553.2. Found: 553.2. ¹H NMR (400 MHz, CD₃OD): δ 7.93-7.89 (3H, m), 7.84 (1H, d, J=8.0 Hz), 7.63 (1H, t, J=8.0 Hz), 6.92-6.90 (2H, m), 6.80 (1H, s), 6.60 (1H, d, J=8.8 Hz), 4.34 (1H, dd, J=14.4 Hz, 2.4 Hz), 3.75-3.69 (1H, m), 3.51 (3H, s), 3.23-3.17 (1H, m), 2.93 (2H, d, J=6.0 Hz), 1.42 (9H, s).

Example 61 Synthesis of (S)-tert-butyl (4-((4-fluorophenyl)sulfonyl)-2-((2-oxopyrrolidin-1-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (61)

A mixture of (S)-(6-((tert-butoxycarbonyl)amino)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl 4-methylbenzenesulfonate (81.6 mg, 0.138 mmol), ethyl 4-aminobutanoate (93 mg, 0.708 mmol), and NMP (1377 μL) was stirred for three days at 100° C. The mixture was cooled, diluted with ethyl acetate and washed with saturated NaHCO₃ and brine. The combined organic layers were dried (MgSO₄) and concentrated. Purification via chromatography eluting with a gradient of 100% hexanes to 100% ethyl acetate afforded (S)-tert-butyl (4-((4-fluorophenyl)sulfonyl)-2-(2-oxopyrrolidin-1-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate. LRMS (ESI) calculated for C₂₀H₂₀FN₃O₆S (M-tBu+H)⁺: 450. Found: 450. ¹H NMR (500 MHz, DMSO-d6) δ 9.29 (s, 1H), 7.86 (s, 1H), 7.78 (m, 2H), 7.43 (t, 2H, J=7.95 Hz), 7.14 (d, 1H, J=8.97 Hz), 6.73 (d, 1H, J=8.96 Hz), 4.16 (d, 1H, J=14.5 Hz), 3.47 (m, 1H), 3.43 (m, 2H), 3.22 (m, 2H), 3.19 (m, 1H), 2.22 (m, 2H), 1.92 (m, 2H), 1.46 (s, 9H).

Example 62 Synthesis of (S)-tert-butyl (2-((1H-pyrazol-1-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (62)

To a suspension of sodium hydride (6.18 mg, 0.154 mmol) in DMF (1 mL) at room temperature was added a solution of 1H-pyrazole (9.01 mg, 0.132 mmol) in DMF (1 mL) and the reaction mixture was stirred for ten minutes. A solution of (R)-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl methanesulfonate (50 mg, 0.088 mmol) in DMF (2 mL) was added and the mixture was heated at 120° C. for fifteen minutes. The mixture was cooled, diluted with ethyl acetate, washed with water and brine, dried (Na₂SO₄), filtered and concentrated. The residue was purified by reverse phase HPLC using a solvent system of MeCN/water with 0.1% trifluoroacetic acid to yield (S)-tert-butyl (2-((1H-pyrazol-1-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate as white solid. MS ESI calculated for C₂₄H₂₅F₃N₄O₂S (M+H)⁺: 539. Found: 539. ¹H NMR (600 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.10-7.88 (m, 4H), 7.79 (t, J=7.9 Hz, 1H), 7.66 (d, J=2.2 Hz, 1H), 7.45 (s, 1H), 7.02 (d, J=6.9 Hz, 1H), 6.68 (d, J=8.9 Hz, 1H), 6.23 (s, 1H), 4.42-4.27 (m, 3H), 3.80 (s, 1H), 3.47 (s, 2H), 3.28 (dd, J=14.2, 9.7 Hz, 1H), 1.43 (s, 9H).

Example 63 Preparation of Additional Heteroatom Linked Heterocycles

The compounds in Table 21 below were prepared based on the experimental procedures described in Examples 61 and 62 and elsewhere in the detailed description, and can be achieved by one of skill in the art in light of the present disclosure. In cases of where two products could be obtained, both were isolated via HPLC chromatography.

TABLE 21 Ex. Observed No. Structure Name m/z 63A

(S)-tert-butyl (2-((2H-1,2,3-triazol-2- yl)methyl-4-((1-(difluoromethyl)-3-methyl- 1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 470.1 (M − tBu)⁺ 63B

(S)-tert-butyl (2-((4H-1,2,4-triazol-4- yl)methyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 540.2 (M + H)⁺ 63C

(S)-tert-butyl (2-((1H-1,2,4-triazol-1- yl)methyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 540.2 (M + H)⁺ 63D

(S)-tert-butyl (2-((1H-1,2,3-triazol-1- yl)methyl)-4-((1-(difluoromethyl)-3-methyl- 1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 526.1 (M + H)⁺ 63E

(S)-tert-butyl (2-((1H-1,2,3-triazol-1- yl)methyl)-4-((3- (trifluoromethyl(phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 540.1 (M + H)⁺ 63F

(S)-tert-butyl (2-((2H-1,2,3-triazol-2- yl)methyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 484.0 (M − tBu)⁺ 63G

(R)-tert-butyl (2-((pyridin-2-yloxy(methyl)- 4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 588.0 (M + Na)⁺ 63H

(S)-tert-butyl (2-((2-oxopyridin-1(2H)- yl)methyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 566.0 (M + H)⁺

Example 64 Synthesis of (S)-tert-butyl (2-((5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (64)

The title compound was prepared according to the procedures described below.

Part I—Synthesis of (S)-tert-butyl (2-(cyanomethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic acid (200 mg, 0.387 mmol), ammonium chloride (41.4 mg, 0.774 mmol) and (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (221 mg, 0.581 mmol) in dichloromethane (5 mL) at room temperature was added N,N′-diisopropylethylamine (0.20 mL, 1.16 mmol) and the mixture was stirred at room temperature for sixty hours. The mixture was concentrated, and then dissolved in DMF (3 mL). To DMF (1 mL) at 0° C. was added phosphoryl trichloride (0.18 mL, 1.94 mmol) dropwise and the mixture was stirred at room temperature for thirty minutes. The crude solution of the amide was added and the mixture was stirred at room temperature for an additional sixteen hours. The reaction mixture was poured into ice, and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride, dried (Na₂SO₄) filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate/hexane (0˜25%) to afford (S)-tert-butyl (2-(cyanomethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate. MS ESI calculated for C₂₂H₂₂F₃N₃O₅S (M+H)⁺: 498. Found: 442 (M-tBu) and 520 (M+Na).

Part II—Synthesis of (S)-tert-butyl (2-(2-(hydroxyamino)-2-iminoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-tert-butyl (2-(cyanomethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (80 mg, 0.16 mmol) in ethanol (5 mL) was added hydroxylamine hydrochloride (22.4 mg, 0.322 mmol) followed by potassium carbonate (66.7 mg, 0.482 mmol) and the mixture was heated at 70° C. for sixteen hours. Additional hydroxamine hydrochloride (20 mg) was added and the mixture was stirred at 80° C. for an additional five hours. The reaction was cooled to room temperature, filtered and washed with methanol. The filtrate was concentrated to afford (S)-tert-butyl (2-(2-(hydroxyamino)-2-iminoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate, which was used without further purification.

Part III—Synthesis of (S)-tert-butyl (2-((5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To the above prepared (S)-tert-butyl (2-(2-(hydroxyamino)-2-iminoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (0.16 mmol) in acetonitrile (5 mL) was added carbonyl diimidazole (36.7 mg, 0.226 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.091 mL, 0.60 mmol). The mixture was stirred at room temperature for three hours. The mixture was concentrated and the residue was purified by reverse phase HPLC using a solvent system of MeCN/water modified with 0.1% trifluoroacetic acid to yield (S)-tert-butyl (2-((5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate as white solid. MS ESI calculated for C₂₃H₂₃F₃N₄O₇S (M+H)⁺: 557. Found: 501 (M-tBu). ¹H NMR (600 MHz, DMSO-d6) δ 12.10 (s, 1H), 9.27 (s, 1H), 8.19-7.94 (m, 4H), 7.82 (d, J=7.7 Hz, 1H), 6.99 (s, 1H), 6.73 (d, J=9.0 Hz, 1H), 4.95 (s, 1H), 4.47 (d, J=14.0 Hz, 2H), 3.32 (m, 1H), 3.01 (d, J=11.1 Hz, 1H), 2.80 (d, J=7.8 Hz, 1H), 1.46 (s, 9H).

Example 65 Synthesis of tert-butyl (2-(2-hydroxy-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (65)

To a stirred solution of 3 M methyl magnesium bromide in THF (0.9 mL, 2.7 mmol) in anhydrous THF (5 mL) was added a solution of methyl 2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate (140 mg, 0.26 mmol) in THF (2 mL) dropwise at 0° C. The mixture was stirred at 0° C. for an hour and then warmed to room temperature. The reaction was stirred for another hour and saturated aqueous ammonium chloride solution (2 mL) was added. The reaction mixture was diluted with brine (20 mL) and extracted twice with ethyl acetate. The combined organic layers were dried (Na₂SO₄) and concentrated. The residue was purified by Prep-HPLC to afford the product as a white solid. LCMS (ESI) calculated for C₂₄H₂₉F₃N₂NaO₆S: (M+Na)⁺: 553.2. Found: 553.0.

Example 66 Synthesis of (S)-tert-butyl (2-((3-hydroxyazetidin-1-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (66)

To a solution of (R)-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl 4-methylbenzenesulfonate (300 mg, 0.467 mmol) in ethanol (7 mL) was added azetidin-3-ol hydrochloride (256 mg, 2.33 mmol) and potassium carbonate (645 mg, 4.67 mmol). The mixture was heated at 100° C. overnight. The reaction mixture was filtered and concentrated. The residue was purified by Prep-TLC (20*20 cm) (petroleum ether/ethyl acetate 1/6) to afford the title compound. LCMS (ESI) calculated for C₂₄H₂₉F₃SN₃O₆ (M+H)⁺: 544.2. Found: 544.0. ¹HNMR (500 MHz, MeOD): δ 7.97-8.07 (4H, m), 7.77 (1H, t, J=8.0 Hz), 7.06 (1H, dd, J=9.0, 2.5 Hz), 6.74 (1H, d, J=9.0 Hz), 4.33-4.39 (2H, m), 3.68-3.71 (1H, m), 3.59-3.62 (1H, m), 3.46-3.48 (1H, m), 3.28-3.31 (1H, m), 2.92-2.96 (2H, m), 2.64-2.68 (2H, m), 1.55 (9H, s).

Example 67 Preparation of Additional Amines of Benzoxazines

The compounds in Table 22 below were prepared based on the experimental procedures described in Example 66 and elsewhere in the detailed description, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 22 Ex. Observed No. Structure Name m/z 67A

(S)-tert-butyl (2-(((3-methyloxetan-3- yl)amino)methyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 558 (M + H)⁺ 67B

tert-butyl ((2S)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-2- (((1,1,1-trifluoropropan-2- yl)amino)methyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 584 (M + NH₄)⁺ 67C

1,1,1-trifluoro-2-methylpropan-2-yl ((2S)- 4-((4-fluorophenyl)sulfonyl)-2-((2- methylazetidin-1-yl)methyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6-yl)carbamate 546.1 (M + H)⁺ 67D

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4- ((4-fluorophenyl)sulfonyl)-2-((3- hydroxyazetidin-1-yl)methyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6-yl)carbamate 548.1 (M + H)⁺ 67E

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2- (azetidin-1-ylmethyl)-4-((4- fluorophenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 532.1 (M + H)⁺

Example 68 Synthesis of (S)-tert-butyl (3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)carbamate (68)

The title compound was prepared according to the procedures described below.

Part I—Synthesis of (S)-methyl 6-((1-methoxy-1-oxopropan-2-yl)oxy)-5-nitronicotinate

To methyl (S)-lactate (5.8 g, 55.4 mmol) and methyl 6-chloro-5-nitropyridine-3-carboxylate (10 g, 46 mmol) in anhydrous tetrahydrofuran (100 mL) under nitrogen with activated molecular sieves at 0° C. was added 1,8-diazabicyclo[5.4.0]undec-7-ene (9 mL, 60 mmol). The solution quickly turned dark, was stirred at 0° C. for thirty minutes, then was allowed to stir at ambient temperature for an hour. A solid precipitated out of solution. The solution was diluted with ethyl acetate, solids were filtered off, and then the filtrates were concentrated. The residue was purified by column chromatography eluting with a gradient of 10-50% ethyl acetate in hexanes to yield the title compound.

Part II—Synthesis of (S)-methyl 3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate

In a three necked round bottomed flask equipped with an overhead stirrer was added (S)-methyl 6-((1-methoxy-1-oxopropan-2-yl)oxy)-5-nitronicotinate (9.09 g, 32 mmol) and acetic acid (100 mL). Powdered iron was carefully added (8.9 g, 160 mmol) and the suspension was heated at 70° C. for 2 hours. The reaction was cooled, filtered through CELITE and washed with 5% methanol in tetrahydrofuran (3×50 mL). The combined filtrates were concentrated to a volume of approximately 50 mL comprising mostly acetic acid and product. Upon the addition of water (100 mL), a solid crashed out, which was slurried and filtered off and washed with water to yield the title compound.

Part III—Synthesis of (S)-3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylic acid

To (S)-methyl 3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate (3.9 g, 17.6 mmol) in tetrahydrofuran (30 mL) and methanol (10 mL) was added 2M sodium hydroxide and the reaction stirred at ambient temperature overnight. The volume was concentrated to 20 mL. The solution was acidified with 1 M hydrogen chloride (40 mL). The resulting solids were slurried for 20 minutes, filtered and dried to yield the title compound.

Part IV—Synthesis of (S)-tert-butyl (3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)carbamate

To a solution of (S)-3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylic acid (2.39 g, 11.5 mmol) in anhydrous toluene (20 mL) and anhydrous tert-butanol (20 mL) with triethylamine (3.5 mL, 25 mmol) was added activated molecular sieves, and the resulting mixture was stirred for fifteen minutes before the addition of diphenylphosphoryl azide (3 mL, 13.8 mmol). The reaction was heated to reflux under nitrogen for two hours. Upon completion, the solution was cooled, filtered over filter paper, diluted with ethyl acetate, washed with water, brine, dried (Na₂SO₄) and concentrated. The residue was purified by column chromatography eluting with a gradient of 20-80% ethyl acetate in hexanes. The resulting product was repurified by column chromatography eluting with a gradient of 0-10% methanol in dichloromethane to yield the title compound.

Part V—Synthesis of (S)-tert-butyl (3-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)carbamate

To a solution of (S)-tert-butyl (3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)carbamate (3.5 g, 12.5 mmol) in anhydrous tetrahydrofuran (40 mL) under nitrogen at 0° C. was added 1 M lithium aluminum hydride in tetrahydrofuran (38 mL, 38 mmol) dropwise. The reaction was stirred at 0° C. for three hours, then at ambient temperature for an hour. The suspension was recooled to 0° C. before carefully quenching it with sodium sulfate decahydrate. The suspension was slurried at ambient temperature for 1 hour before filtering solids off over CELITE. The residue was purified by column chromatography eluting with a gradient of 0.5-5% methanol in dichloromethane to yield the title compound (0.91 g, 27%).

Example 69 Synthesis of [(R)-1-((3-chloro-benzenesulfonyl)-3-hydroxymethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl]-carbamic acid tert-butyl ester (69)

To a solution ((R)-3-hydroxymethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-carbamic acid tert-butyl ester (0.56 g, 2 mmol) in pyridine (5 mL) at 0° C. was added 3-chloro phenyl sulfonyl chloride (0.42 g, 2 mmol). The reaction mixture was stirred at room temperature for two hours. The reaction mixture was diluted with ethyl acetate, washed with brine, saturated sodium bicarbonate and water. The organic layer was separated, dried (Na₂SO₄) and concentrated. The crude product was purified by column chromatography on silica gel (hexanes/AcOEt 2:1 to 1:3) to afford the title compound as a white foam. LCMS (ESI) m/z 456.

Example 70 Synthesis of [(S)-1-(3-Chloro-benzenesulfonyl)-3-(2,4-dioxo-oxazolidin-3-ylmethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl]-carbamic acid tert-butyl ester (70)

To a solution of (91 mg, 0.2 mmol) [(R)-1-((3-chloro-benzenesulfonyl)-3-hydroxymethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl]-carbamic acid tert-butyl ester), oxazolidine-2,4-dione (20 mg, 0.20 mmol), triphenylphosphine (78.6 mg, 0.30 mmol) in THF (2 mL) was added DIAD (60.6 mg, 0.30 mmol) and the mixture was stirred for 12 hours at room temperature. The mixture was concentrated, and the residue was purified by column chromatography to afford [(S)-1-(3-Chloro-benzenesulfonyl)-3-(2,4-dioxo-oxazolidin-3-ylmethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl]-carbamic acid tert-butyl ester. LCMS (ESI) m/z 539.1.

Example 71 Synthesis of 4-[(S)-6-amino-4-((3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl]-1-methyl-piperazin-2-one (71)

The title compound was prepared according to the procedures described below.

Part I—Synthesis of 3-chloro-benzenesulfonic acid (R)-7-tert-butoxycarbonylamino-1-(3-chloro-benzenesulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3-yl methyl ester

To a solution ((R)-3-hydroxymethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-carbamic acid tert-butyl ester (0.56 g, 2 mmol) in pyridine (5 mL) was added 3-chlorobenzenesulphonyl chloride (0.42 g, 2 mmol). The resulting mixture was stirred for 15 minutes at 0° C., and then a second equivalent of sulfonyl chloride was added and stirring continued for an hour. The reaction mixture was diluted with ethyl acetate, washed with water, dried (Na₂SO₄) and concentrated. The residue was purified by column chromatography eluting with hexanes/ethyl acetate 2:1) to afford 3-chloro-benzenesulfonic acid (R)-6-tert-butoxycarbonylamino-4-((3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl ester. LCMS (ESI) m/z 630.3.

Part II—Synthesis of 4-[(S)-6-amino-4-((3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl]-1-methyl-piperazin-2-one

A suspension of 3-chloro-benzenesulfonic acid (R)-6-tert-butoxycarbonylamino-4-((3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl methyl ester (63 mg, 0.1 mmol), N,N′-diisopropylethylamine (2 eq), 1-methyl-piperazin-2-one hydrochloride salt (30 mg, 0.2 mmol) and potassium iodide (cat.) in THF/NMP (0.5 mL) was heated in a sealed tube for 12 h at 80° C. The mixture was partitioned between water and ethyl acetate. The organic layer was separated, washed with brine, saturated NaHCO₃ and concentrated. The residue was purified by column chromatography on silica gel to provide [(S)-4-((3-chloro-benzenesulfonyl)-2-(4-methyl-3-oxo-piperazin-1-ylmethyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic acid tert-butyl ester. LCMS (ESI) m/z 551.

Example 72 Synthesis of (S)-tert-butyl (5-((4-fluorophenyl)sulfonyl)-6-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate (72)

The title compound was prepared according to the procedures described below.

Part I—Synthesis of 1-benzyl-7-bromo-2-methyl-1,2,3,4-tetrahydro-1,5-naphthyridine

To a solution of 1-benzyl-7-bromo-3,4-dihydro-1,5-naphthyridin-2(1H)-one (1.42 g, 4.48 mmol) in anhydrous tetrahydrofuran (20 mL) under a nitrogen atmosphere at 0° C. was added 1M methylmagnesium bromide in tetrahydrofuran (17.9 mL, 17.9 mmol) slowly. The resulting red solution was stirred at ambient temperature for 2 hours, then the solution was heated for 2 hours to 50° C. To the cooled solution was slowly added acetic acid (6 mL). The resulting mixture was stirred for two minutes, then was added sodium borohydride (0.42 g, 11.2 mmol). The reaction was stirred at ambient temperature overnight. The reaction mixture was basified with 2M sodium hydroxide (12 mL), and extracted with ethyl acetate twice. The combined extracts were washed with brine, dried with sodium sulfate, filtered, and concentrated in the presence of silica. The residue was purified by column chromatography eluting with a gradient of ethyl acetate in hexanes to yield the title compound.

Part II—Synthesis of tert-butyl (5-benzyl-6-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

1-Benzyl-7-bromo-2-methyl-1,2,3,4-tetrahydro-1,5-naphthyridine (0.56 g, 1.77 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.04 g, 0.09 mmol), tripotassium phosphate (1.1 g, 5.3 mmol), and tert-butyl carbamate (0.31 g, 2.6 mmol) were combined in toluene (5 mL) and water (1 mL). The reaction was degassed, then treated with tris(dibenzylideneacetone)dipalladium(0) (0.08 g, 0.09 mmol) and refluxed overnight. The solution was cooled, partitioned between ethyl acetate and brine, separated, dried (Na₂SO₄) and concentrated in the presence of silica. The residue was purified by column chromatography eluting with a gradient of ethyl acetate in hexane to yield the title compound.

Part III—Synthesis of tert-butyl (6-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

To a degassed suspension of tert-butyl (5-benzyl-6-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate (0.26 g, 0.74 mmol) and ammonium formate (0.93 g, 14.7 mmol) under a nitrogen atmosphere in methanol (5 mL) was added 10% palladium on carbon (78 mg). The suspension was refluxed for three hours. The reaction was cooled to ambient temperature, filtered through CELITE, rinsing with methanol and concentrated. The residue was redissolved in ethyl acetate, washed with water, brine, dried with sodium sulfate, filtered and concentrated to yield the title compound.

Part IV—Synthesis of (S)-tert-butyl (5-((4-fluorophenyl)sulfonyl)-6-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

To a solution of tert-butyl (6-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate (0.13 g, 0.49 mmol) in anhydrous pyridine (2 mL) was added 4-fluorobenzenesulfonyl chloride (0.14 g, 0.74 mmol) and the reaction was heated at 60° C. for 8 hours. The reaction was cooled, diluted with ethyl acetate, washed with 10% citric acid, water, and brine. The organics were dried with sodium sulfate, filtered and concentrated in the presence of silica. The residue was purified by column chromatography eluting with a gradient of methanol in dichloromethane. The purified racemic mixture was separated by preparatory chiral HPLC to yield the title compounds. ¹H NMR (400 Hz, DMSO-d6) δ 9.59 (s, 1H), 8.34 (s, 1H), 8.16 (s, 1H), 7.61 (m, 2H), 7.37 (m, 2H), 4.37 (m, 1H), 2.5 (m, 1H), 2.06 (m, 1H), 1.57 (m, 1H), 1.46 (s, 9H), 1.12 (m, 3H).

Example 73 Synthesis of (S)-benzyl tert-butyl (1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate (73)

The title compound was prepared according to the procedures described below.

Part I—Synthesis of methyl 5-amino-6-chloronicotinate

To methyl 6-chloro-5-nitro-pyridine-3-carboxylate (2.0 g, 9.2 mmol) in anhydrous methanol (30 mL) under nitrogen was added tin (II) chloride (5.3 g, 28 mmol). The resulting mixture was refluxed for eighteen hours. Then, the reaction mixture was cooled and then poured carefully into a stirred slurry of CELITE in saturated sodium bicarbonate at 0° C. The resulting suspension was stirred for twenty minutes before the mixture was filtered through CELITE to remove the solids. The solids were washed with ethyl acetate, and the filtrates were collected, washed with water, and washed with brine. The resulting organic solution was dried with sodium sulfate (Na₂SO₄) and concentrated to provide the title compound.

Part II—Synthesis of methyl 7-((tert-butoxycarbonyl)amino)-6-oxo-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxylate

An oven-dried flask was charged with zinc powder (2.0 g, 30 mmol) and iodine (0.12 g, 0.46 mmol), and flushed with nitrogen. Next, the flask was cooled in an ice bath and a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-iodo-propanoate (5.0 g, 15 mmol) in anhydrous N,N-dimethylformamide (20 mL) was added to the flask. The resulting reaction mixture was stirred at 0° C. for 90 minutes. Then, solid methyl 5-amino-6-chloronicotinate (3.7 g, 19.7 mmol) was added followed by addition of dichlorobistriphenyl-phosphine palladium (II) (0.53 g, 0.76 mmol). Then, the reaction mixture was heated at 40° C. for 18 hours. Next, the reaction mixture was filtered through CELITE, washing with ethyl acetate. The resulting organic solution was concentrated in vacuo to provide a residue that was redissolved in N,N-dimethylformamide (20 mL). To the resulting organic solution, potassium carbonate (2.5 g, 18 mmol) was added and the reaction mixture was heated at 80° C. for 2 hours. The resulting solution was partitioned between ethyl acetate and saturated ammonium chloride. The organic layer was separated and washed with water and brine. The resulting organic solution was dried with sodium sulfate, filtered, and concentrated in vacuo to provide a residue that was purified by column chromatography eluting with a gradient of 20-100% ethyl acetate in hexanes to provide the title compound.

Part III—Synthesis of 7-((tert-butoxycarbonyl)amino)-6-oxo-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxylic acid

To (R)-methyl 7-((tert-butoxycarbonyl)amino)-6-oxo-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxylate (2.63 g, 8.2 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) was added 2M sodium hydroxide (12 mL, 24 mmol). The reaction mixture was stirred at ambient temperature for two hours. Then, the volume of the reaction mixture was reduced in vacuo. The resulting solution was partitioned between ethyl acetate and 10% citric acid. The organic layer was isolated, washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo to yield the title compound.

Part IV—Synthesis of benzyl tert-butyl (2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate

To (R)-7-((tert-butoxycarbonyl)amino)-6-oxo-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxylic acid (2.07 g, 6.74 mmol) in anhydrous toluene (20 mL) and benzyl alcohol (2.1 mL, 20 mmol) was added activated 4A molecular sieves and triethylamine (2.1 mL, 14.8 mmol). The resulting mixture was stirred at ambient temperature for 10 minutes, then diphenylphosphorylazide (1.7 mL, 8.1 mmol) was added. Next, the resulting suspension was refluxed for 2 hours. Then, the reaction mixture was filtered hot through CELITE, washing with ethyl acetate. The resulting organic solution was concentrated onto silica in vacuo to provide a residue that was purified by column chromatography eluting with a gradient of methanol in dichloromethane to provide the title compound.

Part V—Synthesis of benzyl tert-butyl (1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate

To a solution of benzyl tert-butyl (2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate (5.35 g, 13 mmol) in anhydrous tetrahydrofuran (140 mL) under nitrogen at 0° C. was added solid lithium aluminum hydride (2.5 g, 65 mmol) in portions. After complete addition of the lithium aluminum hydride, the cooling bath was removed and the reaction was stirred at ambient temperature for 3 hours. The reaction was recooled to 0° C. before carefully quenching it with water (2.5 mL), 15% sodium hydroxide (2.5 mL), then water (7.5 mL). The solids were filtered through CELITE and washed with tetrahydrofuran, and then the filtrates were concentrated in the presence of silica. The residue was purified by column chromatography eluting with a gradient of methanol in dichloromethane to yield the title compound.

Part VI—Synthesis of (S)-benzyl tert-butyl (1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate

To (S)-benzyl tert-butyl (1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate (0.28 g, 0.70 mmol) in anhydrous pyridine (4 mL) was added 4-fluorobenzenesulfonyl chloride (0.17 g, 0.88 mmol) and the mixture was heated at 60° C. for 4 hours. The mixture was cooled, diluted with ethyl acetate, washed with citric acid, water, brine, dried with sodium sulfate, filtered and concentrated in the presence of silica. The residue was purified by column chromatography eluting with a gradient of methanol in dichloromethane to yield the title compound. LRMS (ESI) calculated for C₂₇H₃₀FN₄O₆S (M+H)⁺: 557. Found: 557.

Example 74 Preparation of additional sulfonamides from benzyl tert-butyl (1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate

The compounds in Table 24 below were prepared based on the experimental procedures described in Example 73 and elsewhere in the detailed description, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 24 Ex. Observed No. Structure Name m/z 74A

benzyl tert-butyl (1-((3- (trifluoromethyl)phenyl)sulfonyl)-1,2,3,4- tetrahydro-1,5-naphthyridine-3,7- diyl)dicarbamate 629.17 (M + Na)⁺ 74B

benzyl tert-butyl (1-((3- cyanophenyl)sulfonyl)-1,2,3,4-tetrahydro- 1,5-naphthyridine-3,7-diyl)dicarbamate 586.14 (M + Na)⁺ 74C

benzyl tert-butyl (1-((1-(difluoromethyl)-3- methyl-1H-pyrazol-4-yl)sulfonyl)-1,2,3,4- tetrahydro-1,5-naphthyridine-3,7- diyl)dicarbamate 615.19 (M + Na)⁺

Example 75 Synthesis of (S)-benzyl (5-((4-fluorophenyl)sulfonyl)-7-(2-oxopyrrolidin-1-yl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate (75)

Part 1—Synthesis of (S)-benzyl (7-amino-5-((4-fluorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

The carbamate from Example 73 was separated by chiral chromatography to afford the two isomers. Products from the first to elute are isomer A, while products from the second to elute are isomer B. To a solution of (S)-benzyl tert-butyl (1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate (0.34 g, 0.61 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (2 mL) and the reaction was stirred at ambient temperature for 2 hours. The reaction was concentrated and dissolved in ethyl acetate, washed with saturated sodium bicarbonate, brine, dried (Na₂SO₄) and concentrated to yield the title compound. LRMS (ESI) calculated for C₂₂H₂₂FN₄O₄S (M+H)⁺: 457. Found: 457.

Part 2—Synthesis of (S)-benzyl (5-((4-fluorophenyl)sulfonyl)-7-(2-oxopyrrolidin-1-yl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

To a solution of (S)-benzyl (7-amino-5-((4-fluorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate (135 mg, 0.3 mmol) in dichloromethane (1.5 mL) and tetrahydrofuran (1.5 mL) was added tetraalkylammonium carbonate resin (0.49 g, 1.5 mmol) followed by 4-chlorobutyryl chloride (99 μL, 0.89 mmol) and the resulting solution was shaken at ambient temperature for 4 hours. The resin was filtered off and the filtrate was concentrated in the presence of silica. The crude product was purified by column chromatography eluting with a gradient of methanol in dichloromethane. The material was redissolved in anhydrous tetrahydrofuran (3 mL) under a nitrogen atmosphere, cooled to −78° C., then treated with 1M potassium tert-butoxide in tetrahydrofuran (0.59 mL, 0.59 mmol). After 20 minutes the reaction was warmed to 0° C. After 20 minutes the reaction was quenched by adding silica gel and concentrated. The residue was purified by column chromatography eluting with a gradient of methanol in dichloromethane to yield the title compound. LRMS (ESI) calculated for C₂₆H₂₆FN₄O₅S (M+H)⁺: 525. Found: 525.

Example 76 Synthesis of (S)-neopentyl (5-((4-fluorophenyl)sulfonyl)-7-(2-oxopyrrolidin-1-yl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate and (R)-neopentyl (5-((4-fluorophenyl)sulfonyl)-7-(2-oxopyrrolidin-1-yl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate (Example Nos. 76A and 76B)

The title compounds were prepared according to the procedures described below.

Part I—Synthesis of (S)-1-(7-amino-1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)pyrrolidin-2-one

To a degassed suspension of (S)-benzyl (5-((4-fluorophenyl)sulfonyl)-7-(2-oxopyrrolidin-1-yl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate from Example 75 (60 mg, 0.11 mmol) and ammonium formate (72 mg, 1.1 mmol) in methanol (4 mL) under a nitrogen atmosphere was added 10% palladium on carbon (12 mg) and the reaction was refluxed for 2 hours. The reaction was cooled to ambient temperature, then filtered through a CELITE cartridge washing through with methanol. The solution was concentrated to yield the title compound, which was used without further purification.

Part II—Synthesis of (S)-neopentyl (5-((4-fluorophenyl)sulfonyl)-7-(2-oxopyrrolidin-1-yl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

To a solution of (S)-1-(7-amino-1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)pyrrolidin-2-one (28 mg, 0.7 mmol) in tetrahydrofuran (1 mL) was added N,N-diisopropylethylamine (56 μL, 0.22 mmol) followed by neopentyl chloroformate (16 μL, 0.11 mmol). The reaction was shaken at ambient temperature for 1 hour, then concentrated onto silica. The residue was purified by column chromatography eluting with a gradient of methanol in dichloromethane to yield the title compound. ¹H NMR (400 Hz, DMSO-d6) δ 9.89 (s, 1H), 8.39 (s, 1H), 8.27 (s, 1H), 7.37 (m, 2H,), 7.83 (m, 2H), 7.41 (m, 2H), 4.04-3.97 (m, 2H), 3.80 (s, 2H), 3.61 (m, 1H), 3.3-3.2 (m, 2H), 2.88 (m, 1H), 2.72 (m, 1H), 2.21 (m, 2H), 1.85 (m, 2H), 0.93 (s, 9H).

The enantiomeric compound, Example. No. 76B, was prepared in an analogous manner.

Example 77 Synthesis of tert-butyl (5-((4-fluorophenyl)sulfonyl)-7-hydroxy-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate (77)

The title compound was prepared according to the procedures described below.

Part I—Synthesis of 1-benzyl-7-bromo-3-hydroxy-3,4-dihydro-1,5-naphthyridin-2(1H)-one

To a solution of 1-benzyl-7-bromo-3,4-dihydro-1,5-naphthyridin-2(1H)-one (0.9 g, 2.8 mmol) in anhydrous tetrahydrofuran (3 mL) under a nitrogen atmosphere at −78° C. was added 1M lithium bis(trimethylsilyl)amide solution in tetrahydrofuran (6.2 mL, 6.2 mmol). After stirring the resulting solution for 5 minutes, (2R,8aS)-(+)-(camphorylsulfonyl)oxaziridine (0.72 g, 3.1 mmol) was added and the reaction was stirred at −78° C. for 10 minutes, before removing the cooling bath. The solution was stirred at ambient temperature for 2 hours then quenched with 10% citric acid, extracted with ethyl acetate, washed with brine, dried with sodium sulfate, filtered and concentrated. The residue was purified by column chromatography eluting with a gradient of 30-100% ethyl acetate in hexanes. The residue was triturated with ethyl acetate/hexane mixture. The filtered solids were washed with hexanes and dried to yield the title compound.

Part II—Synthesis of 1-benzyl-7-bromo-1,2,3,4-tetrahydro-1,5-naphthyridin-3-ol

To a solution of 1-benzyl-7-bromo-3-hydroxy-3,4-dihydro-1,5-naphthyridin-2(1H)-one (0.3 g, 0.9 mmol) in anhydrous tetrahydrofuran (6 mL) under nitrogen was added borane dimethylsulfide complex (0.36 mL, 3.6 mmol) and the reaction was refluxed for 1 hour. The reaction was next cooled to ambient temperature, treated with methanol (3 mL) and refluxed for 10 minutes, before being concentrated and dissolved in ethyl acetate, washed with water, brine, dried (Na₂SO₄) and concentrated to yield the title compound.

Part III—Synthesis of 1-benzyl-7-bromo-3-((tert-butyldimethylsilyl)oxy)-1,2,3,4-tetrahydro-1,5-naphthyridine

To a solution of 1-benzyl-7-bromo-1,2,3,4-tetrahydro-1,5-naphthyridin-3-ol (0.26 g, 0.81 mmol) in dichloromethane (3 mL) under nitrogen was added 2,6-lutidine (0.24 mL, 2.0 mmol) followed by tert-butyldimethylsilyl trifluoromethanesulfonate (0.21 mL, 0.9 mmol). The reaction was stirred at ambient temperature for two hours. Additional tert-butyldimethylsilyl trifluoromethanesulfonate (0.1 mL, 0.45 mmol) was added and the reaction was stirred for an additional hour, before the addition of silica. The residue was purified by column chromatography eluting with a gradient of ethyl acetate in hexanes to yield the title compound.

Part IV—Synthesis of tert-butyl (5-benzyl-7-((tert-butyldimethylsilyl)oxy)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

1-benzyl-7-bromo-3-((tert-butyldimethylsilyl)oxy)-1,2,3,4-tetrahydro-1,5-naphthyridine (0.28 g, 0.65 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (15 mg, 0.03 mmol), tripotassium phosphate (0.41 g, 1.9 mmol), and tert-butyl carbamate (0.11 g, 0.97 mmol) were combined in toluene (5 mL) and water (1 mL). The reaction was degassed, then treated with tris(dibenzylideneacetone)dipalladium(0) (30 mg, 0.03 mmol). The solution was refluxed overnight. The solution was cooled, partitioned between ethyl acetate and brine, separated, dried, filtered and concentrated in the presence of silica. The residue was purified by column chromatography eluting with a gradient of ethyl acetate in hexane to yield the title compound.

Part V—Synthesis of tert-butyl (7-((tert-butyldimethylsilyl)oxy)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

To a degassed suspension of tert-butyl (5-benzyl-7-((tert-butyldimethylsilyl)oxy)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate (0.11 g, 0.23 mmol) and ammonium formate (0.15 g, 2.3 mmol) under a nitrogen atmosphere in methanol (4 mL) was added 10% palladium on carbon (25 mg). The suspension was refluxed for 3 hours. The reaction was cooled to ambient temperature, filtered through CELITE, rinsing with methanol. Concentrated filtrates were dissolved in ethyl acetate, washed with water, brine, dried with sodium sulfate (Na₂SO₄) and concentrated to yield the title compound.

Part VI—Synthesis of tert-butyl (7-((tert-butyldimethylsilyl)oxy)-5-((4-fluorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

To tert-butyl (7-((tert-butyldimethylsilyl)oxy)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate (85 g, 0.22 mmol) in anhydrous pyridine (1 mL) was added 4-fluorobenzenesulfonyl chloride (65 mg, 0.34 mmol) and the resulting solution was heated to 70° C. for 4 hours. Upon completion, the reaction was cooled, diluted with ethyl acetate, washed with citric acid, water, brine, dried with sodium sulfate, filtered and concentrated in the presence of silica. The residue was purified by column chromatography eluting with a gradient of methanol in dichloromethane to yield the title compound.

Part VII—Synthesis of tert-butyl (5-((4-fluorophenyl)sulfonyl)-7-hydroxy-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

To a solution of tert-butyl (7-((tert-butyldimethylsilyl)oxy)-5-(4-fluorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate (45 mg, 0.084 mmol) in anhydrous tetrahydrofuran (2 mL) under nitrogen was added 1M tetrabutylammonium fluoride in tetrahydrofuran (0.17 mL, 0.17 mmol). The reaction was stirred at ambient temperature for one hour, then partitioned between ethyl acetate and brine, dried with sodium sulfate, filtered and concentrated in the presence of silica. The residue was purified by column chromatography eluting with a gradient of methanol in dichloromethane to yield the title compound. ¹H NMR (400 Hz, DMSO-d6) δ 9.55 (s, 1H), 8.29 (m, 1H), 8.14 (s, 1H), 7.85 (m, 2H), 7.38 (m, 2H), 5.24 (m, 1H), 3.85 (m, 2H), 3.58 (m, 1H), 2.8 (m, 1H), 2.53 (m, 1H), 1.45 (s, 9H).

Example 78 Synthesis of (R)-neopentyl (5-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-7-(hydroxymethyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate and (S)-neopentyl (5-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-7-(hydroxymethyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate (Example Nos. 78A and 78B)

The title compound was prepared according to the procedures described below.

Part I—Synthesis of 1-benzyl-7-bromo-3,4-dihydro-1,5-naphthyridin-2(1H)-one

To 7-bromo-3,4-dihydro-1,5-naphthyridin-2(1H)-one (8.1 g, 35.7 mmol) in N,N-dimethylformamide (50 mL) was added cesium carbonate (23.2 g, 71.4 mmol) followed by benzyl bromide (5.1 mL, 42.8 mmol). This mixture was stirred at 70° C. overnight. The solution was cooled, diluted with ethyl acetate, washed with water, brine, dried with sodium sulfate, filtered and concentrated. The residue was recrystallized from ethyl acetate/hexanes, and rinsed with hexanes to afford the title compound.

Part II—Synthesis of methyl 1-benzyl-7-bromo-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carboxylate

To 1-benzyl-7-bromo-3,4-dihydro-1,5-naphthyridin-2(1H)-one (4.6 g, 14.5 mmol) in anhydrous tetrahydrofuran (50 mL) under nitrogen at −78° C. was added lithium hexamethyldisilazane (1 M in tetrahydrofuran, 29 mL, 29 mmol), and the mixture was stirred for 5 minutes at −78° C. To the anion formed was added methyl chloroformate (1.2 mL, 16 mmol) and this mixture was stirred at −78° C. for an additional 30 minutes. The mixture was allowed to warm to ambient temperature, quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, washed with brine, dried with sodium sulfate, filtered and concentrated to yield the title compound.

Part III—Synthesis of (1-benzyl-7-bromo-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methanol

To a solution of methyl 1-benzyl-7-bromo-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carboxylate (5.35 g, 14.3 mmol) in anhydrous tetrahydrofuran (40 mL) under nitrogen at ambient temperature was carefully added BH₃—SMe₂ (10 M in tetrahydrofuran, 5.7 mL, 57 mmol). After this addition, the reaction was refluxed for 90 minutes, then cooled to 0° C. and carefully quenched with methanol (30 mL), then refluxed for a further 10 minutes. The solution was cooled and concentrated. The residue was diluted in ethyl acetate, washed with water, brine, dried with sodium sulfate, and concentrated to yield the title compound.

Part IV—Synthesis of 1-benzyl-7-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,3,4-tetrahydro-1,5-naphthyridine

To a solution of (1-benzyl-7-bromo-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methanol (4.6 g, 13.8 mmol) in dichloromethane (50 mL) was added diisopropylethylamine (5.4 mL, 20.7 mmol), tert-butyldimethylsilyl chloride (2.5 g, 16.6 mmol) and catalytic 4-dimethylaminopyridine (0.17 g, 1.4 mmol) and the resulting mixture was stirred at ambient temperature overnight. The solution was washed with saturated aqueous ammonium chloride, dried (Na₂SO₄), and concentrated in the presence of silica gel. The residue was purified by column chromatography eluting with a gradient of 0-30% ethyl acetate in hexanes to yield the title compound.

Part V—Synthesis of 5-benzyl-7-(((tert-butyldimethylsilyl)oxy)methyl)-N-(diphenylmethylene)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-amine

A suspension of 1-benzyl-7-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,3,4-tetrahydro-1,5-naphthyridine (3.98 g, 8.9 mmol), benzophenone imine (1.8 mL, 10.7 mmol), cesium carbonate (4.3 g, 13.3 mmol), X-Phos (0.21 g, 0.44 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.4 g, 0.44 mmoL) in anhydrous 1,4-dioxane (50 mL) was first degassed, then heated at 110° C. under nitrogen overnight. The solution was cooled, diluted with ethyl acetate, filtered through CELITE, and concentrated in the presence of silica gel. The residue was purified by column chromatography eluting with a gradient of 5-40% ethyl acetate in hexanes to yield the title compound.

Part VI—Synthesis of 5-benzyl-7-(((tert-butyldimethylsilyl)oxy)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-amine

To a degassed suspension of 5-benzyl-7-(((tert-butyldimethylsilyl)oxy)methyl)-N-(diphenylmethylene)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-amine (3.7 g, 6.8 mmol) and ammonium formate (8.5 g, 135 mmol) under nitrogen in methanol (75 mL) was added 10% palladium on carbon (0.7 g, 0.68 mmol). This mixture was refluxed under nitrogen for 2 hours. The reaction was cooled to ambient temperature and filtered through CELITE, rinsing with methanol. The filtrates were concentrated under reduced pressure, redissolved in ethyl acetate, washed with water, then brine, dried with sodium sulfate, filtered and concentrated in the presence of silica gel. Purification by column chromatography eluting with a gradient of ethanol in dichloromethane yielded the title compound.

Part VII—Synthesis of tert-butyl (5-benzyl-7-(((tert-butyldimethylsilyl)oxy)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

A mixture of 5-benzyl-7-(((tert-butyldimethylsilyl)oxy)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-amine (3.83 g, 10 mmol), triethylamine (2.02 g, 20 mmol), and di-tert-butyl dicarbonate (2.73 g, 12.5 mmol) in dichloromethane (50 mL) was stirred at room temperature for 2 days. The reaction mixture was partitioned between dichloromethane and water. The aqueous layer was re-extracted with dichloromethane, and the combined organic layers were dried (Na₂SO₄) and concentrated to afford the title compound, which was used without further purification.

Part VIII—Synthesis of [7-(tert-butyl-dimethyl-silanyloxymethyl)-5,6,7,8-tetrahydro-[1,5]naphthyridin-3-yl]-carbamic acid tert-butyl ester

[5-Benzyl-7-(tert-butyl-dimethyl-silanyloxymethyl)-5,6,7,8-tetrahydro-[1,5]naphthyridin-3-yl]-carbamic acid tert-butyl ester (5.9 g, 12.2 mmol) was dissolved in methanol (100 mL) and 10% Pd/C catalyst (1.0 g) was added, followed by ammonium formate (5 g). The mixture was heated at reflux for 24 hours. The cooled mixture was filtered through a pad of CELITE and the filtrate was evaporated. The residue was purified by SiO₂ chromatography to afford the title compound. LC/MS (ESI) m/z 394.4. This material was separated by chiral SPC chromatography into its two enantiomers. Compounds derived from the first enantiomer to elute are named with an “A” in the name. The following experimental procedures are illustrative of the chemistry employed separately for each of the two enantiomers.

Part IX—Synthesis of [7-(tert-butyl-dimethyl-silanyloxymethyl)-5-(4-fluorobenzenesulfonyl)-5,6,7,8-tetrahydro-[1,5]naphthyridin-3-yl]-carbamic acid tert-butyl ester

To a solution [7-(tert-butyl-dimethyl-silanyloxymethyl)-5,6,7,8-tetrahydro-[1,5]naphthyridin-3-yl]-carbamic acid tert-butyl ester (0.394 g, 1 mmol), 4-dimethylaminopyridine (0.061 g, 0.5 mmol) in pyridine (15 mL) was added 1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl chloride (0.277 g, 1.2 mmol). The reaction was heated at 60° C. for 4 hours. The reaction was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel to give [7-(tert-butyl-dimethyl-silanyloxymethyl)-5-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-5,6,7,8-tetrahydro-[1,5]naphthyridin-3-yl]-carbamic acid tert-butyl ester. LC/MS(ESI) m/z 588.5.

The enantiomeric compound was prepared in an analogous manner.

Example 79 Preparation of additional sulfonamides from 7-(hydroxymethyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamates

The compounds in Table 25 below were prepared based on the experimental procedures described in Examples 77 and 78 and elsewhere in the detailed description, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 25 Ex. Observed No. Structure Name m/z 79A

tert-butyl (7-(hydroxymethyl)-5-(m- tolylsulfonyl)-5,6,7,8-tetrahydro-1,5- naphthyridin-3-yl)carbamate 434 (M + H)⁺ 79B

tert-butyl (5-((3,4-difluorophenyl)sulfonyl)-7- (hydroxymethyl)-5,6,7,8-tetrahydro-1,5- naphthyridin-3-yl)carbamate 456 (M + H)⁺ 79C

(R or S)-neopentyl (5-((4- fluorophenyl)sulfonyl)-7-(hydroxymethyl)- 5,6,7,8-tetrahydro-1,5-naphthyridin-3- yl)carbamate 452 (M + H)⁺ 79D

(S or R)-neopentyl (5-((4- fluorophenyl)sulfonyl)-7-(hydroxymethyl)- 5,6,7,8-tetrahydro-1,5-naphthyridin-3- yl)carbamate 452 (M + H)⁺

Example 80 Synthesis of neopentyl ((S)-5-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate (Examples 80A and 80B)

The title compound was prepared according to the procedures described below.

Part I—Synthesis of (R)-(1-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-7-(((neopentyloxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl methanesulfonate

To a solution (R)-neopentyl (5-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-7-(hydroxymethyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate (0.28 g, 0.59 mmol) in dichloromethane (5 mL) was added triethylamine (0.248 mL, 1.77 mmol) and methanesulfonic acid anhydride (0.153 g, 0.88 mmol). The mixture was stirred at room temperature for four hours, then concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was dried (Na₂SO₄) and concentrated to afford the title compound.

Part II—Synthesis of neopentyl ((S)-5-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

A mixture (R)-(1-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-7-(((neopentyloxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl methanesulfonate (0.10 g, 0.18 mmol) and (R)-pyrrolidine-3-ol (31.3 mg, 0.36 mmol) in THF with triethylamine (10 uL) was heated at 70° C. for 12 hours. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried (Na₂SO₄) and concentrated. The residue was purified by column chromatography eluting with dichloromethane/MeOH/triethylamine (89:10:1) to give the title compound, Example No. 80A. LRMS (ESI) calculated for C₂₄H₃₅F₂N₆O₅S (M+H)⁺: 557. Found: 557.

Ex. No. 80B was prepared in an analogous manner using the enantiomer of the starting alcohol. LRMS (ESI) calculated for C₂₄H₃₅F₂N₆O₅S (M+H)⁺: 557. Found: 557.

Example 81 Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl ((R or S)-4-((3,4-difluorophenyl)sulfonyl)-2-((S or R)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Examples 81A, 81B, and 81C)

To a solution of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl 4-(3,4-difluorophenylsulfonyl)-2-(2,2,2-trifluoroacetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylcarbamate (260 mg, 0.47 mmol) in 10 mL of MeOH was added NaBH₄ (35 mg, 0.93 mmol) and the resulting mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried over Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the crude mixture of diastereomers as a yellow solid. LCMS (ESI): calculated for C₂₁H₁₇F₈N₂O₆S [M+H]⁺: 579. found [M+H]⁺: 579.

The mixture of diastereomers was separated by chiral SFC to afford three eluents: First Isomer (Peak 1, Example 81A): as a white solid, ¹H-NMR (MeOD, 400 MHz) δ 7.98 (1H, s), 7.72-7.74 (1H, m), 7.58 (1H, br s), 7.47-7.51 (1H, m), 7.08-7.11 (1H, m), 6.78 (1H, d, J=8.8 Hz), 4.40-4.43 (1H, m), 4.08-4.11 (1H, m), 3.62-3.65 (1H, m), 3.51-3.54 (1H, m), 1.77 (6H, s); Second Isomer (Peak 2, Example 81B): as a white solid, ¹H-NMR (MeOD, 400 MHz) δ 7.97 (1H, s), 7.79-7.81 (1H, m), 7.60-7.62 (1H, m), 7.45-7.49 (1H, m), 7.09-7.12 (1H, m), 6.80-7.00 (1H, m), 4.45-4.50 (1H, m), 4.21-4.24 (1H, m), 3.68-3.70 (1H, m), 3.38-3.42 (1H, m), 1.77 (6H, s); Third Isomer (Peak 3, Example 81C): as a white solid, ¹H-NMR (MeOD, 400 MHz) δ 7.97 (1H, s), 7.79-7.81 (1H, m), 7.60-7.62 (1H, m), 7.45-7.49 (1H, m), 7.09-7.12 (1H, m), 6.80-7.00 (1H, m), 4.45-4.50 (1H, m), 4.21-4.24 (1H, m), 3.68-3.70 (1H, m), 3.38-3.42 (1H, m), 1.77 (6H, s).

The compounds in Table 26 below were prepared based on the methods described in Example X and elsewhere in the description, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 26 Ex. Observed No. Structure Name m/z 81D

1,1,1-trifluoro-2-methylpropan-2-yl ((R or S)-4-((3-chloro-1-ethyl-1H- pyrazol-4-yl)sulfonyl)-2-((S or R)- 2,2,2-trifluoro-1-hydroxyethyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 612 (M + NH₄)+ 81E

1,1,1-trifluoro-2-methylpropan-2-yl ((R or S)-4-((3-chloro-1-ethyl-1H- pyrazol-4-yl)sulfonyl)-2-((S or R)- 2,2,2-trifluoro-1-hydroxyethyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 595 (M + H)+ 81F

1,1,1-trifluoro-2-methylpropan-2-yl ((R or S)-4-((3-chloro-1-ethyl-1H- pyrazol-4-yl)sulfonyl)-2-((S or R)- 2,2,2-trifluoro-1-hydroxyethyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 595 (M + H)+ 81G

1,1,1-trifluoro-2-methylpropan-2-yl ((S and R)-4-((4- fluorophenyl)sulfonyl)-2-((S and R)- 2,2,2-trifluoro-1-hydroxyethyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 561 (M + H)+

Example 82 Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl ((S)-2-((R)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate, 1,1,1-trifluoro-2-methylpropan-2-yl ((S)-2-((S)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate, 1,1,1-trifluoro-2-methylpropan-2-yl ((R)-2-((R)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate, 1,1,1-trifluoro-2-methylpropan-2-yl ((R)-2-((S)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Examples 82A, 82B, 82C, and 82D)

Step 1—Preparation of (S and R)-2,2,2-trifluoro-1-((R and S)-4-((4-fluorophenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl trifluoromethanesulfonate

To a solution of 1,1,1-trifluoro-2-methylpropan-2-yl ((S and R)-4-((4-fluorophenyl)sulfonyl)-2-((S and R)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (600 mg, 1.07 mmol) in 25 mL/2.5 mL of DCM/pyridine was added Tf₂O (480 mg, 1.70 mmol) at 0° C. and the resulted mixture was stirred at 0° C. for 1 hour. 1 N HCl was then added and the mixture was extracted 3× with DCM. The combined organic layers were washed with brine, dried over Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the crude title compound as a yellow oil, which was used in the next step without further purification. ¹H-NMR (MeOD, 400 MHz) δ 7.95-7.97 (1H, m), 7.75-7.82 (2H, m), 7.28-7.33 (2H, m), 7.18-7.19 (1H, m), 6.82-6.84 (1H, m), 5.92-6.01 (1H, m), 4.51-4.57 (1H, m), 3.86-3.91 (1H, m), 3.36-3.44 (1H, m), 1.77 (6H, s).

Step 2—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl ((R and S)-2-((S and R)-1-azido-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S and R)-2,2,2-trifluoro-1-((R and S)-4-((4-fluorophenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl trifluoromethanesulfonate (600 mg, 0.87 mmol) in 20 ml, of DMSO was added NaN₃ (120 mg, 1.85 mmol) and then the resulted mixture was stirred at room temperature for 16 hours. Water was added and the mixture extracted 3× with EtOAc. The aqueous layer was treated with H₂O₂, followed by Na₂SO₃ before being discarded. The organic layer was washed with water, brine, dried over Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as white solid. ¹H-NMR (MeOD, 400 MHz) δ 7.97 (s, 1H), 7.79-7.82 (m, 2H), 7.21-7.31 (m, 2H), 7.14-7.17 (m, 1H), 6.77-6.79 (m, 1H), 4.39-4.49 (m, 1H), 4.35-4.38 (m, 1H), 3.72-3.75 (m, 1H), 3.40-3.47 (m, 1H), 1.77 (s, 6H).

Step 3—Preparation of Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl ((S)-2-((R)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate, 1,1,1-trifluoro-2-methylpropan-2-yl ((S)-2-((S)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate, 1,1,1-trifluoro-2-methylpropan-2-yl ((R)-2-((R)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate, 1,1,1-trifluoro-2-methylpropan-2-yl ((R)-2-((S)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A solution of 1,1,1-trifluoro-2-methylpropan-2-yl ((R and S)-2-((S and R)-1-azido-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (300 mg, 0.51 mmol) and one drop of NH₄OH in 30 mL of MeOH was charged with 150 mg of Pd/C (wet) and the reaction was stirred at room temperature for 16 hours under H₂ balloon atmosphere. The reaction mixture was filtered through CELITE and the filtrate was concentrated to give the crude product as a yellow solid. LCMS (ESI): calculated for C₂₁H₂₁F₇N₃O₅S [M+H]⁺: 560. found: 560.

The mixture was separated by chiral SFC (Chiralcel OD-3 150×4.6 mm I.D., 3 um; Mobile phase: methanol (0.05% DEA) in CO₂ from 5% to 40%) to afford 4 isomers. First Isomer (Peak 1, Example 82A): ¹H-NMR (MeOD, 400 MHz) δ 7.98 (1H, s), 7.79-7.83 (1H, m), 7.25-7.30 (2H, m), 7.10-7.13 (1H, m), 6.76-6.78 (1H, m), 4.47-4.51 (1H, m), 3.56-3.59 (1H, m), 3.43-3.49 (2H, m), 1.77 (6H, s); Second Isomer (Peak 2, Example 82B): ¹H-NMR (MeOD, 400 MHz) δ 7.98 (1H, s), 7.79-7.83 (2H, m), 7.25-7.30 (2H, m), 7.10-7.13 (1H, m), 6.76-6.78 (1H, m), 4.47-4.51 (1H, m), 3.56-3.59 (1H, m), 3.43-3.49 (2H, m), 1.77 (6H, s); Third Isomer (Peak 3, Example 82C): ¹H-NMR (MeOD, 400 MHz) δ 7.97 (1H, s), 7.78-7.81 (2H, m), 7.25-7.29 (2H, m), 7.13-7.15 (1H, m), 6.79-6.81 (1H, m), 4.37-4.41 (1H, m), 3.43-3.58 (3H, m, 3H), 1.77 (6H, s); Fourth Isomer (Peak 4, Example 82D): ¹H-NMR (MeOD, 400 MHz) δ 7.97 (1H, s), 7.78-7.81 (2H, m), 7.25-7.29 (2H, m), 7.13-7.15 (1H, m), 6.79-6.81 (1H, m), 4.37-4.41 (1H, m), 3.43-3.58 (3H, m), 1.77 (6H, s).

Example 83 Preparation of (S)-tert-butyl (2-(2-(ethylsulfonyl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Example 83)

Step 1—Preparation of (S)-methyl 2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate

To a mixture of (S)-methyl 2-(6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate (200 mg, 0.531 mmol) in THF (3 mL) was added 3-(trifluoromethyl)benzene-1-sulfonyl chloride (195 mg, 0.797 mmol) and pyridine (3 mL). The reaction mixture was stirred at 20° C. for 2 hours, then diluted with water (20 mL) and extracted with ethyl acetate (3×15 mL). The organic layers were separated, combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo and the residual oil was purified by prep-TLC (petroleum ether/ethyl acetate=3:1) to afford the title compound as a white solid. LCMS (ESI) calculated for C₂₃H₂₆F₃N₂O₇S [M+H]⁺: 531.1. found: 553.2.

Step 2—Preparation of (S)-tert-butyl (2-(2-hydroxyethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-methyl 2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate (200 mg, 0.377 mmol) in dry methanol (10 mL) was added sodium borohydride (83 mg, 2.262 mmol) at 0° C. The reaction was stirred at 50° C. for 12 hours, then quenched with aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=30:1 to 1:1) to give the title compound as a white solid. LCMS (ESI) calculated for C₂₂H₂₅F₃N₂O₆SNa [M+Na]⁺: 525.1. found: 525.2; ¹H NMR (Methanol-d₄, 400 MHz) δ 7.98-8.04 (3H, m), 7.91 (1H, d, J=8.0 Hz), 7.68-7.73 (1H, m), 6.98 (1H, d, J=7.2 Hz), 6.67 (1H, d, J=8.4 Hz), 4.41-4.44 (1H, m), 3.61-3.66 (3H, m), 3.19-3.25 (1H, m), 1.69-1.74 (2H, m), 1.51 (9H, s).

Step 3—Preparation of (S)-2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl methanesulfonate

To a solution of (S)-tert-butyl (2-(2-hydroxyethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (296 mg, 0.589 mmol), triethylamine (0.411 ml, 2.95 mmol) in dry dichloromethane (10 mL) at 0° C. was added methanesulfonyl chloride (1350 mg, 11.78 mmol). The reaction mixture was stirred at 20° C. for 4 hours, then quenched with water (20 mL). The aqueous layer was extracted with dichloromethane (3×20 mL). The organic layer was dried over sodium sulfate, evaporated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=20:1 to 4:1) to give the title compound as a colorless oil. LCMS (ESI) calculated for C₂₃H₂₇F₃N₂O₈S₂Na [M+Na]⁺: 603.1. found: 603.1.

Step 4—Preparation of (S)-tert-butyl (2-(2-(ethylthio)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl methanesulfonate (160 mg, 0.276 mmol) in EtOH (10 mL) at 0° C. was added sodium ethanethiolate (116 mg, 1.378 mmol). The reaction mixture was stirred at 80° C. for 5 hours, then poured into water and extracted with ethyl acetate (3×30 mL). The organic layer was dried over sodium sulfate, evaporated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=20:1 to 5:1) to give the titled compound as a colorless oil. LCMS (ESI) calculated for C₂₄H₃₀F₃N₂O₅S₂[M+H]⁺: 547.1. found: 547.1.

Step 5—Preparation of (S)-tert-butyl (2-(2-(ethylsulfonyl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-tert-butyl (2-(2-(ethylthio)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (140 mg, 0.256 mmol) in dichloromethane (10 mL) at 0° C. was added metachloroperbenzoic acid (133 mg, 0.768 mmol). The reaction mixture was stirred at 15° C. for 2 hours, then poured into water and extracted with dichloromethane (3×30 mL). The organic layer was dried over sodium sulfate, evaporated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=20:1 to 3:1) to give the titled compound as a colorless oil. LCMS (ESI) calculated for C₂₄H₂₉F₃N₂O₇S₂Na [M+Na]⁺: 601.1. found: 601.0; ¹H NMR (Methanol-d₄, 400 MHz) δ 8.02-8.11 (3H, m), 7.93 (1H, d, J=8.0 Hz), 7.72-7.77 (1H, m), 7.01 (1H, d, J=6.8 Hz), 6.73 (1H, d, J=8.4 Hz), 4.44 (1H, d, J=14.0 Hz), 3.71 (1H, brs), 3.08-3.34 (5H, m), 2.12-2.17 (1H, m), 1.97-2.03 (1H, m), 1.53 (9H, s), 1.33 (3H, t, J=7.6 Hz).

Example 84 Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-(ethylsulfonyl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Example 84)

Step 1—Preparation of (S)-2-(2-(ethylsulfonyl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine

To a solution of (S)-tert-butyl (2-(2-(ethylsulfonyl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (140 mg, 0.242 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2 mL) at 0° C. The reaction mixture was stirred at 15° C. for 2 hours, then evaporated to give the crude title compound as a colorless oil. LCMS (ESI) calculated for C₁₉H₂₂F₃N₂O₅S₂[M+H]⁺: 479.1. found: 479.2.

Step 2—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-(ethylsulfonyl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A mixture of (S)-2-(2-(ethylsulfonyl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine (50 mg, 0.104 mmol) and 3-methyl-1-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-1H-imidazol-3-ium iodide (49.6 mg, 0.209 mmol) in DMSO (3 mL) was stirred at 15° C. for 1 hour. The reaction mixture was directly purified by Prep-HPLC, eluting with Acetonitrile/Water+0.10% TFA, to give the titled compound as a white solid. LCMS (ESI) calculated for C₂₄H₂₇F₆N₂O₇S₂ [M+H]⁺: 633.1. found: 633.0; ¹H NMR (Methanol-d₄, 400 MHz) δ 8.06-8.13 (3H, m), 7.92 (1H, d, J=8.0 Hz), 7.71 (1H, t, J=8.0 Hz), 7.01 (1H, d, J=6.8 Hz), 6.73 (1H, d, J=8.8 Hz), 4.43 (1H, d, J=12.4 Hz), 3.75 (1H, brs), 3.04-3.35 (5H, m), 2.12-2.16 (1H, m), 1.97-2.02 (1H, m), 1.75 (6H, s), 1.30 (3H, t, J=7.6 Hz).

Example 85 Synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl ((2S,3R)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3-methyl-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Example 85)

Step 1—Synthesis of (R and S)-ethyl 3-methyl-6-nitro-2H-benzo[b][1,4]oxazine-2-carboxylate

Into a 2000-mL 3-necked round-bottom flask was placed a solution of 2-amino-4-nitrophenol (80 g, 519.06 mmol, 1.00 equiv) in 1,4-dioxane (1000 mL), potassium carbonate (143 g, 1.03 mol, 2.00 equiv) and ethyl 2-chloro-3-oxobutanoate (170 g, 1.03 mol, 2.00 equiv). The resulting solution was stirred for 2 h at 100° C. in an oil bath, then cooled to 25° C., diluted with 3000 mL of H₂O and stirred for 1 h at room temperature. The solids were collected by filtration and the crude solid was dried and stirred in 600 mL of ether for 2 h at room temperature. The solids were collected by filtration to yield ethyl 3-methyl-6-nitro-2H-1,4-benzoxazine-2-carboxylate as a red solid.

Step 2—Synthesis of ((2S,3S,2S,3R,2R,3S and 2R,3R)-3-methyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methanol

Into a 3000-mL 3-necked round-bottom flask was placed a solution of (R and S)-ethyl 3-methyl-6-nitro-2H-benzo[b][1,4]oxazine-2-carboxylate (105 g, 397.37 mmol, 1.00 equiv) in ethanol (1500 mL), followed by the addition of NaBH₄ (44 g, 1.16 mol, 3.00 equiv), in portions over 30 min. The resulting solution was stirred for 3 h at 40° C., then quenched by the addition of 1500 mL of water. The resulting mixture was extracted with 3×1500 mL of ethyl acetate and the combined organic layers washed with 3×1000 mL of saturated brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound as a red syrup.

Step 3—Synthesis tert-butyl ((2R,3R)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate and tert-butyl ((2S,3S)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

Into a 2000-mL round-bottom flask was placed a solution of (3-methyl-6-nitro-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methanol (80 g, 356.80 mmol, 1.00 equiv) in ethyl acetate (1200 mL), Palladium on carbon (8 g, 0.10 equiv) and (Boc)₂O (116 g, 531.50 mmol, 1.50 equiv). The resulting solution was stirred for 4 h at 40° C. in an oil bath under an atmosphere of hydrogen, then filtered. The filtrate was concentrated under vacuum and the crude product was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (5:1 to 1:1). Prep-SFC separation was conducted under the following conditions: Column, ChiralPak IC, 5×25 cm, Sum; mobile phase, CO₂ (65%), IPA (with 0.2% DEA) (35%). Detector, UV 220 nm to afford tert-butyl N-[(2S,3S)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate as a white solid and of tert-butyl N-[(2R,3R)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate as a white solid.

tert-butyl ((2S,3S)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

LC-MS (ES, m/z) calculated for C₁₅H₂₃N₂O₄ [M+H]⁺: 295. found 295 [α]_(D) ²⁰=+51.3 (c=1.0 g/100 mL MeOH); ¹H-NMR (300 MHz, CDCl₃, ppm): δ 6.93 (s, 1H), 6.75-6.22 (d, 1H), 6.46-6.42 (m, 1H), 6.28 (s, 1H), 4.25-4.20 (m, 1H), 3.87-3.80 (m, 1H), 3.73-3.69 (m, 1H), 3.61-3.58 (m, 1H), 1.49 (s, 9H), 1.20-1.17 (d, 3H).

tert-butyl ((2R,3R)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

LC-MS (ES, m/z) calculated for C₁₅H₂₃N₂O₄ [M+H]⁺: 295. found 295 [α]_(D) ²⁰=−51.1 (c=1.0 g/100 mL MeOH); ¹H-NMR (300 MHz CDCl₃, ppm): δ 6.93 (s, 1H), 6.75-6.22 (d, 1H), 6.46-6.42 (m, 1H), 6.28 (s, 1H), 4.25-4.20 (m, 1H), 3.87-3.80 (m, 1H), 3.73-3.69 (m, 1H), 3.61-3.58 (m, 1H), 1.49 (s, 9H), 1.20-1.17 (d, 3H).

Step 4—Synthesis ((2R,3R)-6-((tert-butoxycarbonyl)amino)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl 1-(difluoromethyl)-3-methyl-1H-pyrazole-4-sulfonate

To a microwave vial equipped with a stir bar was added tert-butyl ((2R,3R)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (500 mg, 1.699 mmol), 1-(difluoromethyl)-3-methyl-1H-pyrazole-4-sulfonyl chloride (1959 mg, 8.49 mmol) and pyridine (10 mL). The vial was sealed and the reaction heated to 60° C. for 1 h. Upon completion, the reaction mixture was extracted with 3×IPA/CHCl₃ (1:3 v/v) and NaHCO₃ and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 100% hexanes to 40% ethyl acetate gradient to afford the title product as a white solid. LCMS (ESI): calculated for C₂₁H₂₃F₄N₆O₈S₂[M-tBu+H]⁺: 627. found: 627.

Step 5—Synthesis tert-butyl ((2S,3R)-2-(azidomethyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a microwave vial equipped with a stir bar was added ((2R,3R)-6-((tert-butoxycarbonyl)amino)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl 1-(difluoromethyl)-3-methyl-1H-pyrazole-4-sulfonate (950 mg, 1.392 mmol), DMF (16 ml) and sodium azide (452 mg, 6.96 mmol). The vial was sealed and the reaction heated to 80° C. for 1 h. Upon completion, the reaction mixture was extract 3×IPA/CHCl₃ (1:3, v/v) and saturated NaHCO₃, and the combined organic layer dried and concentrated to afford the crude title compound, which was taken forward without further purification. LCMS (ESI): calculated for C₁₆H₁₈F₂N₇O₅S [M-tBu+H]⁺: 458. found: 458.

Step 6—Synthesis of tert-butyl ((2S,3R)-2-(aminomethyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a flask equipped with a stir bar was added tert-butyl ((2S,3R)-2-(azidomethyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (715 mg, 1.392 mmol), ethyl acetate (21 ml), MeOH (7 ml) and 10% Pd/C (44.5 mg, 0.418 mmol) under a strong flow of nitrogen. The reaction flask was purged 3× with hydrogen and stirred under H₂ balloon atmosphere for 3 h. Upon completion, the reaction mixture was filtered through CELITE and the filtrate concentrate under vacuum. The crude product was taken forward without further purification. LCMS (ESI): calculated for C₁₆H₂₀F₂N₅O₅S [M-tBu+H]⁺: 432. found: 432.

Step 7—Synthesis tert-butyl ((2S,3R)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3-methyl-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a microwave vial equipped with a stir bar was added tert-butyl ((2S,3R)-2-(aminomethyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (30 mg, 0.062 mmol), DIEA (0.043 mL, 0.246 mmol), and DCM (1 mL), followed by methylsulfamoyl chloride (15.95 mg, 0.123 mmol). The reaction was allowed to stir at room temperature for 1 h and then extracted with 3× ethyl acetate and saturated NaHCO₃. The combined organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound, which was taken forward without further purification. LCMS (ESI): calculated for C₁₇H₂₃F₂N₆O₇S₂ [M-tBu+H]⁺: 525. found: 525.

Step 8—Synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl ((2S,3R)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3-methyl-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

Tert-butyl ((2S,3R)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3-methyl-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (35.7 mg, 0.061 mmol) was stirred with 4M HCl in dioxane (0.461 ml, 1.845 mmol) for 1 h at room temperature. Upon completion, the reaction was concentrated and dried under vacuum to afford the intermediate aniline, which was next dissolved in DMF (1.0 mL) before the addition of 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (27.3 mg, 0.123 mmol). The reaction mixture was heated to 80° C. for 1 h, then quenched by the addition of 3 drops of water. The resulting mixture was dissolved in 2 mL of DMSO, filtered and directly purified by reverse phase HPLC (MeCN/water using TFA buffer) to afford the desired product as a white solid. LCMS (ESI): calculated for C₂₁H₂₈F₅N₆O₇S₂[M+H]⁺: 635. found: 635. ¹H-NMR (CDCl₃, 400 MHz) δ 9.75 (s, 1H), 8.68 (s, 1H), 7.90 (m, 1H), 7.63 (t, 1H), 7.28 (m, 1H), 7.18 (m, 1H), 6.80 (m, 2H), 4.57 (m, 1H), 3.60 (m, 1H), 2.90-3.05 (m, 2H), 2.40 (m, 3H), 2.05 (s, 3H), 1.68 (s, 6H), 0.98 (m, 3H).

Example 86 Synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl N-[(2S,3R)-2-[(1S)-1-[[(benzyloxy)carbonyl]amino]ethyl]-4-[(3,4-difluorobenzene)sulfonyl]-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate (Example 86)

Step 1—Synthesis of (2S,3S,4R)-4-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)-2-methylpentanoic acid

Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of known (JACS, 2003, 8218) (2S,3S,4R)-4-[[(tert-butoxy)carbonyl]amino]-3-hydroxy-2-methylpentanoic acid (9.88 g, 39.95 mmol, 1.00 equiv) in dichloromethane (200 mL), 2,6-dimethylpyridine (12.8 g, 119.46 mmol, 3.00 equiv). This was followed by the addition of TBSOTf (26.4 g, 100.00 mmol, 2.50 equiv) dropwise with stirring at −78° C. The resulting solution was stirred for 60 min at −78° C. The reaction was then quenched by the addition of water/ice. The resulting solution was extracted with 3×200 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The resulting crude intermediate was diluted with 150 mL of methanol. Then 50 mL of K₂CO₃ (0.5 M) was added and stirring was continued for an additional 60 min at room temperature. The pH value of the solution was adjusted to 2 with hydrogen chloride (1 N) and the resulting mixture was extracted with 3×300 mL of ethyl acetate. The organic layers were combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to afford (2S,3S,4R)-4-[[(tert-butoxy)carbonyl]amino]-3-[(tert-butyldimethylsilyl)oxy]-2-methylpentanoic acid as a white solid. ¹H-NMR (CDCl₃, 400 MHz) δ 4.48 (br s, 1H), 4.05 (m, 1H), 3.78 (m, 1H), 2.63 (m, 1H), 1.25-1.10 (m, 8H), 0.90 (m, 13H), 0.30 (m, 8H).

Step 2—Synthesis of benzyl tert-butyl ((2R,3S,4S)-3-((tert-butyldimethylsilyl)oxy)pentane-2,4-diyl)dicarbamate

Into a 50-mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of (2S,3S,4R)-4-[[(tert-butoxy)carbonyl]amino]-3-[(tert-butyldimethylsilyl)oxy]-2-methylpentanoic acid (1.8 g, 4.98 mmol, 1.00 equiv) in toluene (20 mL), DPPA (1.38 g, 5.01 mmol, 1.00 equiv) and TEA (1.0 g, 9.88 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at 60° C. Then phenylmethanol (1.62 g, 14.98 mmol, 3.00 equiv) and TEA (1.0 g, 9.88 mmol, 2.0 eq.) were added and stirring was continued for an additional 3 days at 90° C. The reaction was then quenched by the addition of water. The resulting mixture was extracted with 3×50 mL of ethyl acetate and the organic layers combined, washed with 2×30 mL of brine, dried and concentrated. The crude product was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10) to afford tert-butyl N-[(2S,3S,4S)-4-[[(benzyloxy)carbonyl]amino]-3-[(tert-butyldimethylsilyl)oxy]pentan-2-yl]carbamate as a colorless oil, which was used in the next step without further purification.

Step 3—Synthesis of benzyl tert-butyl ((2R,3S,4S)-3-hydroxypentane-2,4-diyl)dicarbamate

Into a 50-mL round-bottom flask, was placed a solution of tert-butyl N-[(2R,3S,4R)-4-[[(benzyloxy)carbonyl]amino]-3-[(tert-butyldimethylsilyl)oxy]pentan-2-yl]carbamate (1.3 g, 2.79 mmol, 1.00 equiv) in tetrahydrofuran (20 mL), TBAF (1.46 g, 5.58 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at room temperature, then concentrated under vacuum. The crude product was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2) to afford tert-butyl N-[(2S,3S,4R)-4-[[(benzyloxy)carbonyl]amino]-3-hydroxypentan-2-yl]carbamate as a colorless oil, which was used in the next step without further purification.

Step 4—Synthesis of benzyl tert-butyl ((2R,3S,4S)-3-(2-bromo-4-nitrophenoxy)pentane-2,4-diyl)dicarbamate

Into a 50-mL 3-necked round-bottom flask, was placed tert-butyl N-[(2R,3S,4S)-4-[[(benzyloxy)carbonyl]amino]-3-hydroxypentan-2-yl]carbamate (950 mg, 2.70 mmol, 1.00 equiv), followed by the addition of sodium hydride (324 mg, 8.10 mmol, 3.00 equiv) in several batches at 0° C. To this was added tetrahydrofuran (20 mL) and 2-bromo-1-fluoro-4-nitrobenzene (768 mg, 3.49 mmol, 1.30 equiv). The resulting solution was stirred for 30 min at 0° C. and at room temperature for 12 h. The reaction was then quenched by the addition of 20 mL of water/ice and the resulting mixture was extracted with 3×30 mL of ethyl acetate. The crude product was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20-1:1) to afford tert-butyl N-[(2R,3S,4S)-4-[[(benzyloxy)carbonyl]amino]-3-(2-bromo-4-nitrophenoxy)pentan-2-yl]carbamate as a yellow solid.

Step 5—Synthesis of benzyl ((2S,3R,4R)-4-amino-3-(2-bromo-4-nitrophenoxy)pentan-2-yl)carbamate

Into a 25-mL round-bottom flask was placed a solution of tert-butyl N-[(2R,3S,4S)-4-[[(benzyloxy)carbonyl]amino]-3-(2-bromo-4-nitrophenoxy)pentan-2-yl]carbamate (450 mg, 0.81 mmol, 1.00 equiv) in dichloromethane (10 mL) and CF₃COOH (3 mL). The resulting solution was stirred for 2 h at room temperature, then quenched with saturated NaHCO₃ (aq.). The resulting mixture was extracted with DCM (20 mL×3) and the combined organic layers concentrated under vacuum to afford benzyl N-[(2S,3R,4R)-4-amino-3-(2-bromo-4-nitrophenoxy)pentan-2-yl]carbamate as a yellow solid, which was carried forward without further purification.

Step 6—Synthesis of benzyl ((2S,3S,4R)-3-(2-bromo-4-nitrophenoxy)-4-(3,4-difluorophenylsulfonamido)pentan-2-yl)carbamate

Into a 25-mL round-bottom flask was placed benzyl N-[(2S,3R,4R)-4-amino-3-(2-bromo-4-nitrophenoxy)pentan-2-yl]carbamate (350 mg, 0.77 mmol, 1.00 equiv), TEA (233 mg, 2.30 mmol, 3.00 equiv), 4-dimethylaminopyridine (9.4 mg, 0.08 mmol, 0.10 equiv) and 3,4-difluorobenzene-1-sulfonyl chloride (246 mg, 1.16 mmol, 1.50 equiv). The resulting mixture was stirred overnight at room temperature, then concentrated under vacuum. The crude product was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20-100:1) to afford benzyl N-[(2S,3S,4R)-3-(2-bromo-4-nitrophenoxy)-4-[(3,4-difluorobenzene)sulfonamido]pentan-2-yl]carbamate as a yellow solid.

Step 7—Synthesis of benzyl ((S)-1-((2S,3R)-4-((3,4-difluorophenyl)sulfonyl)-3-methyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)carbamate

Into a 25-mL round-bottom flask was placed a solution of benzyl N-[(2S,3S,4R)-3-(2-bromo-4-nitrophenoxy)-4-[(3,4-difluorobenzene)sulfonamido]pentan-2-yl]carbamate (320 mg, 0.51 mmol, 1.00 equiv) in MeCN (10 mL), CuI (10 mg, 0.051 mmol, 0.1 equiv), potassium carbonate (140.8 mg, 1.02 mmol, 2.00 equiv) and 1-N,2-N-dimethylcyclohexane-1,2-diamine (14 mg, 0.1 mmol, 0.2 equiv). The resulting solution was stirred overnight at 70° C., then concentrated under vacuum. The crude product was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20-100:1) to afford benzyl N-[(1S)-1-[(2S,3R)-4-[(3,4-difluorobenzene)sulfonyl]-3-methyl-6-nitro-3,4-dihydro-2H-1,4-benzoxazin-2-yl]ethyl]carbamate as a yellow solid, which was used in the next step without further purification.

Step 8—Synthesis of benzyl ((S)-1-((2S,3R)-6-amino-4-((3,4-difluorophenyl)sulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)carbamate

Into a 25-mL round-bottom flask was placed benzyl ((S)-1-((2S,3R)-4-((3,4-difluorophenyl)sulfonyl)-3-methyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)carbamate (110 mg, 0.19 mmol, 1.00 equiv), Raney-Ni (80 mg), methanol (5 mL) and hydrazine hydrate (0.2 mL). The resulting solution was stirred at room temperature for 20 min, then the solids were filtered out and the filtrate concentrated under vacuum to afford the crude title compound as a yellow solid, which was used in the next step without further purification.

Step 9—Synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl N-[(2S,3R)-2-[(1S)-1-[[(benzyloxy)carbonyl]amino]ethyl]-4-[(3,4-difluorobenzene)sulfonyl]-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate

Into a 25-mL round-bottom flask was placed benzyl N-[(1S)-1-[(2S,3R)-6-amino-4-[(3,4-difluorobenzene)sulfonyl]-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl]ethyl]carbamate (130 mg, 0.25 mmol, 1.00 equiv), TEA (25 mg, 0.25 mmol, 1.00 equiv) and 1,1,1-trifluoro-2-methylpropan-(4-nitrophenyl) carbonate (60 mg, 0.25 mmol, 1.0 eq.) in THF (5 mL). The resulting solution was stirred for 6 days at 60° C., then concentrated under vacuum. The crude product was purified by prep-HPLC (MeCN/water using TFA buffer) to afford 1,1,1-trifluoro-2-methylpropan-2-yl N-[(2S,3R)-2-[(1S)-1-[[(benzyloxy)carbonyl]amino]ethyl]-4-[(3,4-difluorobenzene)sulfonyl]-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate as a white solid. ¹H-NMR (CD₃OD, 400 MHz) δ 8.02 (s, 1H), 7.77 (m, 1H), 7.58 (m, 1H), 7.45-7.32 (m, 6H), 7.08 (m, 1H), 6.80 (m, 1H), 5.20 (m, 2H), 4.68 (m, 1H), 3.65 (m, 1H), 3.27 (m, 1H), 1.79 (s, 6H), 1.26 (m, 3H), 1.13 (m, 3H).

Example 87 Preparation of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl (3-(acetamidomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Example 87)

Step 1—Preparation of (R and S)-4-((4-fluorophenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazine-3-carboxylic acid

A mixture of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((4-fluorophenyl)sulfonyl)-3-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (310 mg, 0.63 mmol), PhI(OAc)₂ (507 mg, 1.57 mmol) and TEMPO (196 mg, 1.26 mmol) in CH₃CN/H₂O (5 mL/5 mL) was stirred at room temperature overnight. The reaction was diluted with water, extracted with EtOAc and the combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated. The crude product was purified by silica gel column chromatography (DCM:MeOH=10:1) to afford the title product as a yellow oil. LCMS (ESI): calculated for C₂₀H₁₉F₄N₂O₇S [M+H]⁺: 507. found: 507; ¹H NMR (400 MHz, CDCl₃) δ 7.80-7.84 (2H, m), 7.16 (2H, t, J=8.4 Hz), 7.07 (1H, d, J=8.0 Hz), 6.77 (1H, d, J=8.4 Hz), 6.67 (1H, brs), 5.20 (1H, brs), 4.63 (1H, d, J=10.0 Hz), 3.59 (3H, dd, J=11.2, 2.5 Hz), 1.75 (6H, s).

Step 2—Preparation of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl (3-carbamoyl-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A mixture of (R and S)-4-((4-fluorophenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazine-3-carboxylic acid (15 mg, 0.03 mmol), HATU (14 mg, 0.036 mmol), NH₄Cl (2 mg, 0.036 mmol) and DIPEA (11 mg, 0.09 mmol) in DMF (1 mL) was stirred at room temperature overnight. The reaction was diluted with water, extracted 3× with EtOAc and the combined extracts were washed with brine, dried over Na₂SO₄ and concentrated. The crude product was purified by prep-HPLC (petroleum ether:EtOAc=1.5:1) to afford the title product as a clear oil. LCMS (ESI): calculated for C₂₀H₂₀F₄N₃O₆S [M+H]⁺: 506. found: 506; ¹H NMR (400 MHz, CDCl₃) δ 8.03 (1H, br s), 7.68 (2H, dd, J=8.8, 5.2 Hz), 7.17 (3H, t, J=8.4 Hz), 6.80 (1H, d, J=9.2 Hz), 6.74 (1H, brs), 6.45 (1H, brs), 5.55 (1H, brs), 4.89 (1H, brs), 4.71 (1H, dd, J=11.2, 1.6 Hz), 3.10 (1H, dd, J=11.2, 3.2 Hz), 1.78 (6H, s).

Step 3—Preparation of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl (3-(aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl (3-carbamoyl-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (50 mg, 0.10 mmol) in THF (5 mL) was added dropwise BH₃.SMe₂(75 mg, 0.99 mmol) at 0° C. The reaction mixture was stirred at 75° C. for 48 h under N₂ atmosphere. Upon completion, the reaction was diluted with water, extracted 3× with EtOAc and the combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated. The crude product was purified by prep-TLC (petroleum ether:EtOAc=1.5:1) to afford the title product as a clear oil. LCMS (ESI): calculated for C₂₀H₂₂F₄N₃O₅S [M+H]⁺: 492. found: 492; ¹H NMR (400 MHz, CDCl₃) δ 7.79 (1H, d, J=2.4 Hz), 7.60 (2H, dd, J=8.8, 4.8 Hz, 2H), 7.38 (1H, brs), 7.33 (1H, d, J=7.6 Hz), 7.10 (2H, t, J=8.4 Hz), 6.68 (1H, d, J=9.2 Hz, 1H), 4.66 (1H, d, J=8.4 Hz), 4.05 (1H, d, J=11.6 Hz), 2.92-3.16 (3H, m), 1.73 (6H, d, J=3.2 Hz).

Step 4—Preparation of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl (3-(acetamidomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A mixture of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl(3-(aminomethyl)-4-((4-fluorophenyl) sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (10 mg, 0.02 mmol), Et₃N (21 mg, 0.20 mmol) and AcCl (8 mg, 0.10 mmol) in DCM (3 mL) was stirred at 0° C. for 1 h. The reaction was then diluted with water and extracted 3× with EtOAc. The organic layers were washed with brine, dried over Na₂SO₄ and concentrated. The crude product was purified by prep-TLC (petroleum ether:EtOAc=1:1) to afford the title product as a yellow solid. LCMS (ESI): calculated for C₂₂H₂₄F₄N₃O₆S [M+H]⁺: 534. found: 534; ¹H NMR (400 MHz, CDCl₃) δ 7.94 (1H, brs), 7.66 (2H, dd, J=8.8, 5.2 Hz), 7.08-7.22 (3H, m), 6.78 (1H, d, J=9.2 Hz), 6.70 (1H, brs), 5.93 (1H, brs), 4.43 (1H, d, J=10.0 Hz), 3.99 (1H, d, J=11.2 Hz), 3.58 (1H, dd, J=14.0, 7.2 Hz), 3.12 (1H, dd, J=11.6, 3.2 Hz), 2.95 (1H, ddd, J=14.4, 10.0, 4.4 Hz), 2.05 (3H, s), 1.78 (6H, s).

Example 88 Preparation of (R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-carbamoylcyclopropyl)methyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate and (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-carbamoylcyclopropyl)methyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Examples 88A and 88B) Step 1—Preparation of (R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-carbamoylcyclopropyl)methyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R or S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-((1-cyanocyclopropyl)methyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Isomer 1 from Example 93, Step 5, 150 mg, 0.279 mmol) in DMSO (2 mL) was added K₂CO₃ (77 mg, 0.558 mmol) and 30% H₂O₂ (0.049 ml, 0.558 mmol) at 25° C. under nitrogen. The reaction mixture was stirred at 25° C. for 18 h, then diluted with ethyl acetate (40 mL) and washed with brine (15 mL×3). The combined organic layers were dried over Na₂SO₄ and evaporated to afford the title compound (Isomer 1 from Step 1) as yellow oil.

The other enantiomer (Isomer 2 from Step 1) was prepared using a similar procedure. Both enantiomers have the same analytical data: LCMS (ESI) calculated for C₂₅H₂₉F₃N₃O₆S [M+H]⁺: 556.1. found: 556.2.

Step 2—Preparation of (R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-carbamoylcyclopropyl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate and (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-carbamoylcyclopropyl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R or S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-carbamoylcyclopropyl)methyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Isomer 1 from Step 1, 150 mg, 0.270 mmol)) in MeOH (15 mL) was added magnesium (131 mg, 5.40 mmol) in one portion at 25° C. under nitrogen. The reaction was stirred at 25° C. for 18 hours, then quenched with saturated NH₄Cl solution (60 mL) and extracted with EtOAc (3×50 mL). The organic layers were combined, dried over Na₂SO₄, filtered and the filtrate concentrated in vacuo. The crude product was purified by prep-TLC (petroleum ether:EtOAc=1:2) to afford the title compound (Isomer 1 from Step 2) as a colorless oil.

The other enantiomer (Isomer 2 from Step 2) was prepared using a similar procedure from Isomer 2 from Step 1. Both enantiomers have the same analytical data: LCMS (ESI) calculated for C₁₈H₂₃F₃N₃O₄ [M+H]⁺: 402.1. found: 402.3.

Step 3—Preparation of (R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-carbamoylcyclopropyl)methyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate and (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-carbamoylcyclopropyl)methyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R or S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-carbamoylcyclopropyl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Isomer 1 from Step 2, 40 mg, 0.100 mmol) in pyridine (2 mL) and THF (2 mL) was added 3-chloro-1-ethyl-1H-pyrazole-4-sulfonyl chloride (45.7 mg, 0.199 mmol). The reaction was stirred at 25° C. for 18 h, then concentrated. The title compound (Isomer 1 from Step 3, Example 88A) was obtained by pre-HPLC (MeCN/water using TFA buffer) as a white solid.

The other enantiomer (Isomer 2 from Step 3, Example 88B) was prepared using a similar procedure from Isomer 2 from Step 2. Both enantiomers have the same analytical data: LCMS (ESI) calculated for C₂₃H₂₈ClF₃N₅O₆S [M+H]⁺: 594.1. found: 594.1; ¹H-NMR (CDCl₃, 400 MHz) δ 8.10 (1H, s), 7.86 (1H, s), 6.84-6.86 (1H, m), 6.74-6.77 (2H, m), 4.36 (1H, d, J=12.0 Hz), 4.05-4.11 (3H, m,), 3.34-3.40 (1H, m), 2.07-2.13 (2H, m), 1.73 (6H, s), 1.43-1.47 (3H, m), 1.23-1.29 (2H, m), 0.77-0.82 (2H, m).

Example 89 Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl ((S)-2-((R)-3-amino-2-cyclopropyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate and 1,1,1-trifluoro-2-methylpropan-2-yl ((S)-2-((S)-3-amino-2-cyclopropyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Examples 89A and 89B)

Step 1—Preparation of (S)-methyl 2-(4-benzyl-6-((tert-butoxycarbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate

To a solution of (S)-methyl 2-(6-((tert-butoxycarbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate (1.3 g, 4.03 mmol) in dimethyl formamide (7 mL) were added potassium carbonate (0.836 g, 6.05 mmol) and (bromomethyl)benzene (1.035 g, 6.05 mmol). The resulting mixture was stirred at 20° C. for 18 h, then diluted with water (150 mL) and extracted with ethyl acetate (3×100 mL). The separated organic layers were washed with brine, dried with Na₂SO₄ and concentrated under reduced pressure to give the crude product which was purified by flash column chromatography (petroleum ether:ethyl acetate=10:1 to 5:1) to give the title compound as a white solid. LCMS (ESI) calculated for C₂₃H₂₉N₂O₅ [M+H]⁺: 413. found: 413. ¹H NMR (400 MHz, CDCl3) 7.28-7.38 (5H, m), 6.78 (1H, br s), 6.72 (1H, d, J=8.61 Hz), 6.59 (1H, d, J=7.43 Hz), 6.24 (1H, brs), 4.54-4.60 (1H, m), 4.37-4.49 (2H, m), 3.69 (3H, s), 3.33 (1H, dd, J=1.96, 11.74 Hz), 3.12 (1H, dd, J=6.85, 11.54 Hz), 2.76 (1H, dd, J=6.85, 15.85 Hz), 2.57 (1H, dd, J=6.26, 16.04 Hz), 1.46 (9H, s).

Step 2—Preparation of (S)-2-(4-benzyl-6-((tert-butoxycarbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic acid

To a solution of (S)-methyl 2-(4-benzyl-6-((tert-butoxycarbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate (2.6 g, 6.30 mmol) in dioxane (26 mL) and water (26 ml) was added lithium hydroxide (0.226 g, 9.46 mmol), and the resulting mixture was stirred at 20° C. for 18 h. The reaction was diluted with water (100 mL), extracted with ethyl acetate (50 mL×3) and the aqueous layer was acidified with hydrochloric acid (1M, 10 mL) to pH=3. The mixture was extracted with ethyl acetate (100 mL) and the combined organic layers were dried (Na₂SO₄), filtered and concentrated under reduced pressure to give the crude title compound as a yellow solid, which was used in next step without further purification. LCMS (ESI) calculated for C₂₂H₂₇N₂O₅ [M+H]⁺: 399. found: 399. ¹H NMR (400 MHz, Methanol-d4) 7.31-7.35 (5H, m), 7.23-7.26 (1H, m), 6.88 (1H, br s), 6.62-6.65 (1H, m), 6.55-6.60 (1H, m), 4.43-4.50 (3H, m), 3.35-3.39 (1H, m), 3.11 (1H, dd, J=7.28, 11.80 Hz), 2.62 (2H, t, J=6.27 Hz), 1.46 (9H, s).

Step 3—Preparation of (S)-tert-butyl (4-benzyl-2-(2-(methoxy(methyl)amino)-2-oxoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-2-(4-benzyl-6-((tert-butoxycarbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic acid (2 g, 5.02 mmol) in dichloromethane (20 mL) were added triethylamine (3.50 ml, 25.10 mmol) and HATU (2.290 g, 6.02 mmol), and the resulting mixture was stirred at 20° C. for 30 min, followed by the addition of N,O-dimethylhydroxylamine (1.533 g, 25.10 mmol). The reaction was stirred at 20° C. for 5 minutes, then concentrated under reduced pressure to give the crude product. Flash column chromatography purification (petroleum ether:ethyl acetate=3:1 to 1:1) afforded the title compound as a yellow oil. LCMS (ESI) calculated for C₂₄H₃₂N₃O₅ [M+H]⁺: 442. found: 442. ¹H NMR (400 MHz, CDCl₃) 7.25-7.33 (5H, m), 6.70 (2H, d, J=8.61 Hz), 6.60 (1H, d, J=7.83 Hz), 6.24 (1H, brs), 4.64 (1H, dd, J=1.76, 6.46 Hz), 4.37-4.51 (2H, m), 3.67 (3H, s), 3.41 (1H, dd, J=1.96, 11.74 Hz), 3.21-3.24 (2H, m), 3.01 (3H, s), 2.61 (1H, dd, J=6.46, 15.85 Hz), 1.46 (9H, s), 1.36 (5H, t, J=7.24 Hz).

Step 4—Preparation of (S)-tert-butyl (4-benzyl-2-(2-cyclopropyl-2-oxoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-tert-butyl (4-benzyl-2-(2-(methoxy(methyl)amino)-2-oxoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (6 g, 13.59 mmol) in THF (30 mL) was added dropwise cyclopropylmagnesium bromide (272 ml, 136 mmol) at 0° C. under N₂. The reaction was stirred for 4 h at 0° C., then quenched with sat. NH₄Cl aqueous (50 mL). The biphasic mixture was extracted with EtOAc (50 mL×3), dried over Na₂SO₄ and concentrated to afford the crude title compound as a yellow solid, which was used in next step without further purification. LCMS (ESI) calculated for C₂₅H₃₁N₂O₄ [M+H]⁺: 423. found: 423. ¹HNMR (400 MHz, CDCl₃) δ 7.28-7.34 (5H, m), 6.76 (1H, br s), 6.71 (1H, d, J=8.8 Hz), 6.60 (1H, d, J=6.8 Hz), 6.21 (1H, br s), 4.62 (1H, d, J=0.8 Hz), 4.43 (2H, q, J=8.0 Hz), 3.33-3.36 (1H, m), 3.01-3.13 (2H, m), 2.77-2.79 (1H, m), 1.93-1.96 (1H, m), 1.47 (9H, s), 1.03-1.06 (2H, m), 0.88-0.90 (2H, m).

Step 5—Preparation of tert-butyl ((S)-4-benzyl-2-((S and R)-2-cyano-2-cyclopropylethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-tert-butyl (4-benzyl-2-(2-cyclopropyl-2-oxoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (4.5 g, 10.65 mmol) and 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (4.16 g, 21.30 mmol) in DME (150 mL) and ethanol (5 mL) was added NaOH (1.278 g, 32.0 mmol) in portions under N₂ at 0° C. The reaction was stirred at 30° C. for 18 h, then diluted with DCM (100 mL), washed with water (60 mL×2) and brine and dried over Na₂SO₄. After concentration, the crude product was purified by silica gel column chromatography (petroleum ether:EtOAc=6:1) to afford the title compound as a yellow oil. LCMS (ESI) calculated for C₂₆H₃₂N₃O₃ [M+H]⁺: 434. found: 434. ¹HNMR (400 MHz, CDCl₃) δ 7.29-7.36 (5H, m), 6.81 (1H, d, J=7.2 Hz), 6.72 (1H, d, J=7.2 Hz), 6.60 (1H, d, J=7.2 Hz), 6.23 (1H, br s), 4.42-4.45 (2H, m), 4.33-4.38 (1H, m), 3.24-3.29 (1H, m), 3.08-3.13 (2H, m), 2.55-2.65 (1H, m), 2.41-2.47 (1H, m), 1.85-2.05 (3H, m), 1.47 (9H, s), 0.63-0.66 (2H, m), 0.41-0.45 (2H, m).

Step 6—Preparation of (R and S)-3-((S)-6-amino-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-cyclopropylpropanamide

To MeOH (10 mL) at 0° C. was added slowly sulfurous dichloride (3 mL, 2.076 mmol) and the mixture was stirred at 0° C. for 30 mins, followed by the addition of tert-butyl ((S)-4-benzyl-2-((S and R)-2-cyano-2-cyclopropylethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (900 mg, 2.076 mmol). The reaction was stirred at 70° C. for 18 h, then quenched with 5 mL of water. The resulting mixture was adjusted to pH=7˜8 with saturated solution of NaHCO₃, extracted with EtOAc (15 mL×3) and dried over Na₂SO₄. Purification by chromatography column (petroleum ether/EtOAc=10:1 to 1:2) afforded the title compound all as black oil. LCMS (ESI) calculated for C₂₁H₂₆N₃O₂ [M+H]⁺: 352. found: 352.

Step 7—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl ((S)-2-((S and R)-3-amino-2-cyclopropyl-3-oxopropyl)-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R and S)-3-((S)-6-amino-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-cyclopropylpropanamide (280 mg, 0.797 mmol) in DMSO (8 mL) was added 1-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-1H-imidazol-3-ium iodide (307 mg, 0.876 mmol), then the reaction was stirred at 20° C. for 1 h. The reaction mixture was extracted with EtOAc and water, washed with brine and dried over Na₂SO₄. The crude product was purified by prep-TLC (petroleum ether/EtOAc=1:1) to afford the title compound as a red oil. LCMS (ESI) calculated for C₂₆H₃₁F₃N₃O₄ [M+H]⁺: 506.2. found: 506.2. ¹H-NMR (CDCl₃, 400 MHz) δ 7.07-7.18 (5H, m), 6.48-6.52 (2H, m), 6.36 (1H, s), 5.53 (2H, d, J=10.8 Hz), 3.92-4.00 (2H, m), 3.06-3.09 (1H, m), 2.92-2.96 (1H, m), 1.62-1.73 (2H, m), 1.54 (6H, s), 0.81-0.83 (1H, m), 0.41 (2H, d, J=8.0 Hz), 0.12-0.16 (1H, m), 0.00-0.02 (1H, m).

Step 8—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((S)-3-amino-2-cyclopropyl-3-oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate and 1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((R)-3-amino-2-cyclopropyl-3-oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of 1,1,1-trifluoro-2-methylpropan-2-yl ((S)-2-((S and R)-3-amino-2-cyclopropyl-3-oxopropyl)-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (100 mg, 0.198 mmol) in EtOAc (10 mL) was added Pd/C (10 mg, 10%). The reaction was stirred under balloon of hydrogen at 20° C. for 8 hours, then filtered and concentrated. Purification by prep-TLC (petroleum ether/EtOAc=1:1) afforded the title mixture of diastereomers as a light yellow oil. LCMS (ESI) calculated for C₁₉H₂₅F₃N₃O₄ [M+H]⁺: 416.1. found: 416.1.

The above mixture was resolved by SFC method (SFC-80 Column: Chiralpak AD, 10 μm, Daicel Chemical Industries, Ltd 250×30 mm I.D., Mobile phase: A: Supercritical CO₂, B: EtOH (25%) (contained 75% NH₃.H₂O) Flow rate: 60 mL/min, Wavelength: 220 nm) to yield two isomers: faster eluent (Isomer 1 from Step 8) and slower eluent (Isomer 2 from Step 8).

Step 9—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((R)-3-amino-2-cyclopropyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate and 1,1,1-trifluoro-2-methylpropan-2-yl ((S)-2-((S)-3-amino-2-cyclopropyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of 1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((S or R)-3-amino-2-cyclopropyl-3-oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Isomer 1 from Step 8, 6 mg, 0.014 mmol) in THF (1 mL) were added pyridine (1 mL) and 3-chloro-1-ethyl-1H-pyrazole-4-sulfonyl chloride (19.85 mg, 0.087 mmol) at room temperature under N₂. The reaction was stirred at 20° C. for 18 h, then concentrated. Purification by prep-HPLC (MeCN/water using TFA buffer) afforded the title compound (Isomer 1, Example 89A) as a white solid. LCMS (ESI) calculated for C₂₄H₃₀ClF₃N₅O₆S [M+H]⁺: 608.1. found: 608.1; ¹H-NMR (CDCl₃, 400 MHz) δ 8.10 (1H, s), 7.84 (1H, s), 6.89 (1H, d, J=7.2 Hz), 6.76 (1H, d, J=9.2 Hz), 6.01 (1H, s), 5.81 (1H, s), 4.31 (1H, d, J=14.4 Hz), 4.12 (2H, q, J=7.2 Hz), 4.02 (1H, s), 3.36 (1H, t, J=12.8 Hz), 2.05-2.15 (3H, m), 1.76 (6H, s), 1.49 (1H, t, J=7.2 Hz), 1.00 (1H, s), 0.66 (2H, d, J=7.6 Hz), 0.32-0.35 (1H, m), 0.22-0.24 (1H, m).

The other isomer (Isomer 2, Example 89B) was prepared using a similar procedure from Isomer 2 from Step 8. LCMS (ESI) calculated for C₂₄H₃₀ClF₃N₅O₆S [M+H]⁺: 608.1. found: 608.1; ¹H-NMR (CDCl₃, 400 MHz) δ 8.10 (1H, s), 7.84 (1H, s), 6.89 (1H, d, J=7.2 Hz), 6.76 (1H, d, J=8.8 Hz), 6.59 (1H, s), 6.14 (1H, s), 5.84 (1H, s), 4.32 (1H, d, J=13.6 Hz), 4.12 (2H, q, J=7.2 Hz), 4.03 (1H, s), 3.37 (1H, t, J=12.0 Hz), 1.85-1.96 (2H, m), 1.76 (6H, s), 1.49 (1H, t, J=7.2 Hz), 1.00 (1H, s), 0.66 (2H, d, J=7.2 Hz), 0.33-0.37 (1H, m), 0.22-0.24 (1H, m).

Example 90 Preparation of (R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate and (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Examples 90A and 90B)

To a solution of (R or S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-cyano-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (see Isomer 1 in Example 94; 40 mg, 0.069 mmol) in DMSO (0.5 ml) were added K₂CO₃ (28.7 mg, 0.208 mmol) and 30% H₂O₂ (0.141 ml, 1.384 mmol) dropwise at 0° C. under nitrogen. After 1 h, another batch of 30% H₂O₂ (0.141 ml, 1.384 mmol) was added. The reaction was stirred at room temperature for 6 h, then quenched with Na₂SO₃, filtered and concentrated. The crude product was purified by prep-HPLC (MeCN/water using TFA buffer) to afford the title product (Isomer 1, Example 90A) as a white solid.

The other enantiomer (Isomer 2, Example 90B)) was prepared using a similar procedure from Isomer 2 in Example 94. Both enantiomers have the same analytical data: LCMS (ESI) calculated for C₂₃H₃₀ClF₃N₅O₆S [M+H]⁺: 596. found: 596. ¹H-NMR (CDCl₃, 400 MHz) δ 8.13 (brs, 1H), 7.86 (br s, 1H), 7.16 (br s, 1H), 6.76 (d, J=7.8 Hz, 1H), 6.65-6.72 (m, 1H), 6.60 (br s, 1H), 6.04 (br s, 1H), 4.23 (d, J=13.3 Hz, 1H), 4.08 (q, J=7.0 Hz, 3H), 3.40 (dd, J=8.6, 13.3 Hz, 1H), 2.00 (dd, J=9.3, 14.4 Hz, 1H), 1.78 (d, J=14.8 Hz, 1H), 1.73 (s, 6H), 1.45 (t, J=7.2 Hz, 3H), 1.30 (s, 6H).

Example 91 Preparation of Additional Amides from Propionic Acids

The compounds in Table 27 below were prepared based on the experimental procedures described in Examples 89 and 90 and elsewhere in the detailed description, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 27 Ex. Observed No. Structure Name m/z 91A

(R)-1,1,1-trifluoro-2- methylpropan-2-yl (2-(3- amino-2,2-dimethyl-3- oxopropyl)-4-((3-chloro-1- ethyl-1H-pyrazol-4- yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 596 (M + H)+ 91B

(S)-1,1,1-trifluoro-2- methylpropan-2-yl (2-(3- amino-2,2-dimethyl-3- oxopropyl)-4-((3-chloro-1- ethyl-1H-pyrazol-4- yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 596 (M + H)+ 91C

2,2,2-trifluoro-1,1- dimethylethyl {(2S)-2-(3- amino-2,2-dimethyl-3- oxopropyl)-4-[(4-fluoro-3- methoxyphenyl)sulfonyl]- 3,4-dihydro-2H-1,4- benzoxazin-6-yl}carbamate 592 (M + H)+ 91D

1,1,1-trifluoro-2- methylpropan-2-yl ((S)-2- ((S or R)-3-amino-2- cyclopropyl-3-oxopropyl)- 4-((4-fluoro-3- methoxyphenyl)sulfonyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 626 (M + Na)+ 91E

1,1,1-trifluoro-2- methylpropan-2-yl ((S)-2- ((S or R)-3-amino-2- cyclopropyl-3-oxopropyl)- 4-((3-ethoxy-1-ethyl-1H- pyrazol-4-yl)sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 618 (M + H)+ 91F

1,1,1-trifluoro-2- methylpropan-2-yl ((S)-2- ((S or R)-3-amino-2- cyclopropyl-3-oxopropyl)- 4-((4-fluoro-3- methoxyphenyl)sulfonyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 604 (M + H)+ 91G

1,1,1-trifluoro-2- methylpropan-2-yl ((S)-2- ((S or R)-3-amino-2- cyclopropyl-3-oxopropyl)-4- ((3-ethoxy-1-ethyl-1H- pyrazol-4-yl)sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 618 (M + H)+ 91H

2,2,2-trifluoro-1,1- dimethylethyl [(2S)-2-(3- amino-2,2-dimethyl-3- oxopropyl)-4-{[5- (trifluoromethyl)pyridin-3- yl]sulfonyl}-3,4-dihydro- 2H-1,4-benzoxazin-6- yl]carbamate 613 (M + H)+ 91i

2,2,2-trifluoro-1,1- dimethylethyl {2-(3-amino- 2,2-dimethyl-3-oxopropyl)- 4-[(3-ethoxy-1-ethyl-1H- pyrazol-4-yl)sulfonyl]-3,4- dihydro-2H-1,4-benzoxazin- 6-yl}carbamate 606 (M + H)+ 91J

2,2,2-trifluoro-1,1- dimethylethyl [2-(3-amino- 2,2-dimethyl-3-oxopropyl)- 4-{[1-ethyl-3-(2- hydroxyethoxy)-1H-pyrazol- 4-yl]sulfonyl}-3,4-dihydro- 2H-1,4-benzoxazin-6- yl]carbamate 622 (M + H)+ 91K

(S)-methyl 2-((4-((2-(3- amino-2,2-dimethyl-3- oxopropyl)-6-((((1,1,1- trifluoro-2-methylpropan-2- yl)oxy)carbonyl)amino)-2H- benzo[b][1,4]oxazin-4(3H)- yl)sulfonyl)-1-ethyl-1H- pyrazol-3-yl)oxy)acetate 650 (M + H)+

Example 92 Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-cyanoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate Example 92

Step 1—Preparation of (R)-4-benzyl-2-(bromomethyl)-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine

To (R)-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methanol (10 g, 33.3 mmol) and perbromomethane (16.56 g, 49.9 mmol) in THF (100 mL) was added triphenylphosphine (21.83 g, 83 mmol) portionwise and the reaction stirred at 30° C. for 2 h. The reaction was cooled, water (50 mL) was added and the resulting biphasic mixture was extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered and the filtrate evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with (petroleum ether:EtOAc=10:1) to give (R)-4-benzyl-2-(bromomethyl)-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine as a yellow solid. LCMS (ESI) calculated for C₁₆H₁₆BrN₂O₃ [M+H]⁺: 363/365. found: 363/365. ¹H NMR (CDCl₃, 400 MHz) δ 7.51-7.60 (m, 2H), 7.20-7.35 (m, 6H), 6.83 (d, J=8.6 Hz, 1H), 4.45 (d, J=4.7 Hz, 2H), 3.27-3.53 (m, 5H).

Step 2—Preparation of (R and S)-methyl 3-((S)-4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-cyanopropanoate

(R)-4-benzyl-2-(bromomethyl)-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (250 mg, 0.6 mmol), methyl 2-cyanoacetate (682 mg, 6.8 mmol) and K₂CO₃ (171 mg, 1.239 mmol) in DMSO (2.5 ml) were stirred at 90° C. for 0.5 h. Upon completion, the reaction solution was filtrated and the filtrate was used in the next step with no further purification. LCMS (ESI) calculated for C₂₀H₂₀N₃O₅ [M+H]⁺: 382 found: 382.

Step 3—Preparation of methyl (S)-3-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanenitrile

To a flask with (R and S)-methyl 3-((S)-4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-cyanopropanoate (250 mg, 0.6 mmol) was added lithium chloride (139 mg, 3.3 mmol) in DMSO (2.5 mL) and the reaction was stirred at 160° C. for 0.5 h. The reaction solution was cooled, water (10 mL) was added and the resulting biphasic mixture was extracted with ethyl acetate (25 mL). The combined organic layers were washed with aqueous ammonium chloride (10 mL), dried (Na₂SO₄), filtered and the solvent was evaporated under reduced pressure. The crude product was purified by prep-TLC eluting with (petroleum ether:EtOAc=5:1 to 3:1) to afford the title compound as a yellow oil. LCMS (ESI) calculated for C₁₈H₁₈N₃O₃ [M+H]⁺: 324. found: 324. ¹H NMR (CDCl₃, 400 MHz,) δ 7.48-7.59 (m, 2H), 7.20-7.36 (m, 5H), 6.81 (d, J=8.6 Hz, 1H), 4.44 (s, 2H), 4.29 (t, J=8.0 Hz, 1H), 3.28 (dd, J=2.1, 11.9 Hz, 1H), 3.09 (dd, J=7.4, 11.7 Hz, 1H), 2.47-2.65 (m, 2H), 1.85-1.95 (m, 2H).

Step 4—Preparation of (S)-3-(6-amino-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanenitrile

Methyl (S)-3-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanenitrile (1.6 g, 4.9 mmol) and Pd/C (1.7 g, 10%) in EtOH (30 ml) were stirred under H₂ at 1 atm at 25° C. for 4 h. Upon completion, the reaction mixture was filtrated and the filtrate concentrated. The crude product (S)-3-(6-amino-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanenitrile was used in next step without further purification. LCMS (ESI) calculated for C₁₁H₁₄N₃O [M+H]+: 204. found: 204. ¹H NMR (CDCl₃, 400 MHz) δ 6.53 (d, J=8.2 Hz, 1H), 5.87-6.04 (m, 2H), 4.07 (t, J=8.2 Hz, 1H), 3.31 (dd, J=2.1, 11.1 Hz, 1H), 3.03-3.14 (m, 1H), 2.53 (t, J=7.2 Hz, 2H), 1.82-2.00 (m, 2H).

Step 5—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyanoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

-   (S)-3-(6-amino-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanenitrile     (1.0 g, 4.9 mmol) and     3-methyl-1-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-1H-imidazol-3-ium     iodide (1.971 g, 5.41 mmol) were stirred at 28° C. in DMSO (20 mL)     for 10 h, then treated with water (150 mL) and extracted with ethyl     acetate (3×100 mL). The combined organic fractions were washed with     aqueous ammonium chloride (20 mL), dried (Na₂SO₄), filtered and the     filtrate evaporated under reduced pressure. The crude product was     purified by column chromatography on silica gel (petroleum     ether:EtOAc=3:1) to give the title product as a brown oil. LCMS     (ESI) calculated for C₁₆H₁₉F₃N₃O₃ [M+H]⁺: 358. found: 358. ¹H NMR     (CDCl₃, 400 MHz) δ 6.83 (br s, 1H), 6.65 (d, J=8.6 Hz, 1H), 6.42 (d,     J=6.2 Hz, 2H), 4.14 (br s, 1H), 3.36 (d, J=11.3 Hz, 1H), 3.10 (dd,     J=7.2, 11.5 Hz, 1H), 2.55 (t, J=7.0 Hz, 2H), 1.82-1.97 (m, 2H), 1.67     (s, 6H).

Step 6—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-cyanoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyanoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (250 mg, 0.7 mmol) and pyridine (332 mg, 4.2 mmol) in DCM (6 mL) was treated with 3-(trifluoromethyl)benzene-1-sulfonyl chloride (513 mg, 2.10 mmol) and the resulting mixture was stirred at 30° C. for 8 h. The reaction was cooled to room temperature, then treated with water (5 mL). The resulting biphasic mixture was extracted with dichloromethane (3×5 mL). The combined organic layers were washed with aqueous ammonium chloride (5 mL), dried (Na₂SO₄), filtered and the filtrate was evaporated under reduced pressure. The crude product was purified by prep-TLC (petroleum ether:EtOAc=3:1) to give the title compound as a white solid. LCMS (ESI) calculated for C₂₃H₂₂F₆N₃O₅S [M+H]⁺: 566. found: 566. ¹H NMR (CDCl₃, 400 MHz) δ 7.99 (br s, 1H), 7.74-7.91 (m, 3H), 7.53-7.68 (m, 1H), 6.99 (dd, J=2.1, 8.8 Hz, 1H), 6.72 (d, J=8.6 Hz, 1H), 6.54 (brs, 1H), 4.20 (d, J=14.0 Hz, 1H), 3.57 (brs, 1H), 3.23 (dd, J=9.3, 14.0 Hz, 1H), 2.47 (t, J=6.8 Hz, 2H), 1.75-1.89 (m, 2H), 1.70 (s, 6H).

Example 93 Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((1-cyanocyclopropyl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate and (R)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((1-cyanocyclopropyl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Examples 93A and 93B)

Step 1—Preparation of 1-allylcyclopropanecarbonitrile

To a solution of cyclopropanecarbonitrile (10 g, 149 mmol) in THF (10 mL) was added LDA (82 ml, 164 mmol) dropwise at 0° C. under nitrogen. After 10 min, the mixture was added dropwise to the solution of 3-bromoprop-1-ene (18.93 g, 157 mmol) in THF (20 mL) at 0° C. The reaction was stirred at 0° C. for 1 h, then quenched with saturated NH₄Cl solution (20 mL) and diluted with water (200 mL). The organic layer was separated and the resulting aqueous solution extracted with DCM (35 mL×3). The combined organic layers were washed with brine, dried over Na₂SO₄ and evaporated to dryness at low temperature (<30° C.). The crude product was purified by silica gel chromatography eluted with pure petroleum ether to afford the title compound as a yellow oil. ¹H-NMR (CD₃OD, 400 MHz) δ 5.83 (tdd, J=6.9, 10.0, 16.8 Hz, 1H), 5.11-5.24 (m, 2H), 2.20 (brs, 2H), 1.18-1.26 (m, 2H), 0.79-0.85 (m, 2H).

Step 2—Preparation of (R and S)-1-(oxiran-2-ylmethyl)cyclopropanecarbonitrile

To a solution of 1-allylcyclopropanecarbonitrile (8 g, 74.7 mmol) in DCM (80 ml) was added m-CPBA (18.19 g, 90 mmol) in portions at 0° C. The reaction was stirred at 25° C. for 30 h, then diluted with DCM (100 mL). The organic layer was washed with 1M NaOH solution (60 mL×3) and brine (60 mL×2), dried over Na₂SO₄ and evaporated to afford the crude title product as a yellow oil, which was used directly in the next step without further purification. ¹H-NMR (CD₃OD, 400 MHz) δ 3.11 (d, J=1.9 Hz, 1H), 2.82 (t, J=4.1 Hz, 1H), 2.56 (dd, J=2.5, 4.1 Hz, 1H), 1.89 (dd, J=5.0, 14.4 Hz, 1H), 1.42-1.54 (m, 1H), 1.20-1.31 (m, 2H), 0.90-0.99 (m, 1H), 0.82-0.88 (m, 1H).

Step 3—Preparation of (R and S)-1-((6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)cyclopropanecarbonitrile

To a solution of N-(2-fluoro-5-nitrophenyl)-4-methylbenzenesulfonamide (1 g, 3.23 mmol) in DMF (10 mL) were added (R and S)-1-(oxiran-2-ylmethyl)cyclopropanecarbonitrile (1 g, 8.13 mmol), N-benzyl-N,N-diethylethanaminium chloride (0.110 g, 0.48 mmol) and potassium carbonate (1.56 g, 11.27 mmol) in one portion at room temperature under nitrogen. The reaction was stirred at 100° C. in a microwave for 2 h. Another two batches were run on the same scale as described above and all three mixtures were cooled to room temperature, combined, diluted with water (400 mL) and extracted with EtOAc (100 mL×4). The combined organic layers were washed with brine, dried over Na₂SO₄ and evaporated to dryness. The crude product was purified by silica column (petroleum ether:EtOAc=5:1 to 3:1) to afford the title product as a yellow solid. LCMS (ESI) calculated for C₂₀H₂₀N₃O₅S [M+H]⁺: 414. found: 414. ¹H-NMR (CDCl₃, 400 MHz) δ 8.75 (br s, 1H), 7.87-8.00 (m, 1H), 7.61 (d, J=8.2 Hz, 2H), 7.31 (d, J=7.8 Hz, 2H), 6.93 (d, J=9.0 Hz, 1H), 4.32 (d, J=14.4 Hz, 1H), 3.82 (br s, 1H), 3.26 (dd, J=9.3, 14.0 Hz, 1H), 2.40 (s, 3H), 1.64-1.81 (m, 2H), 1.32 (brs, 2H), 0.89-0.97 (m, 1H), 0.78-0.85 (m, 1H).

Step 4—Preparation of (R and S)-1-((6-amino-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl) methyl)cyclopropanecarbonitrile

To a solution of (R and S)-1-((6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)cyclopropanecarbonitrile (1.5 g, 3.63 mmol) in EtOAc (30 mL) was added Pd/C (0.6 g, 5.64 mmol) in one portion at room temperature. The reaction was stirred at 25° C. under a H₂ balloon for 8 h, then filtered and evaporated to dryness. The crude title product was used directly in the next step without further purification. LCMS (ESI) calculated for C₂₀H₂₂N₃O₃S [M+H]⁺: 384. found: 384. ¹H-NMR (CDCl₃, 400 MHz) δ 7.55 (d, J=8.2 Hz, 2H), 7.25 (d, J=7.0 Hz, 3H), 6.62 (d, J=8.6 Hz, 1H), 6.44 (dd, J=2.5, 8.4 Hz, 1H), 4.25 (dd, J=1.7, 14.2 Hz, 1H), 3.45-3.56 (m, 1H), 3.14 (dd, J=9.5, 14.2 Hz, 1H), 2.37 (s, 3H), 1.59-1.67 (m, 1H), 1.50-1.59 (m, 1H), 1.20-1.29 (m, 2H), 0.86-0.94 (m, 1H), 0.69-0.79 (m, 1H).

Step 5—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-cyanocyclopropyl)methyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate and (R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-cyanocyclopropyl)methyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R and S)-1-((6-amino-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)cyclopropanecarbonitrile (1.3 g, 3.39 mmol) in DMSO (15 ml) was added 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (1.130 g, 5.09 mmol) in one portion at room temperature under N₂. The reaction was stirred at 90° C. for 8 h, then diluted with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over Na₂SO₄ and evaporated to dryness. The crude product was purified by silica gel column (petroleum ether:EtOAc=5:1) to afford the title compound as a white solid.

The two enantiomers were separated by chiral SFC method (Column: Chiralpak AD 250 mm*30 mm, 10 μm; Mobile phase: 35% MeOH+NH₃.H₂O; Flow rate: 80 mL/min; Wavelength: 280 nm). Both enantiomers (faster eluent Isomer 1 and slower eluent Isomer 2) have the same analytical data: LCMS (ESI) calculated for C₂₅H₂₇F₃N₃O₅S [M+H]⁺: 538. found: 538. ¹H-NMR (CDCl₃, 400 MHz) δ 7.69 (br s, 1H), 7.51 (d, J=8.0 Hz, 2H), 7.21 (d, J=8.0 Hz, 2H), 6.72 (d, J=9.0 Hz, 1H), 6.63 (brs, 1H), 4.19 (dd, J=1.7, 14.3 Hz, 1H), 3.51 (d, J=4.5 Hz, 1H), 3.11 (dd, J=9.5, 14.0 Hz, 1H), 2.33 (s, 3H), 1.70 (s, 6H), 1.58-1.66 (m, 1H), 1.48-1.56 (m, 1H), 1.17-1.26 (m, 2H), 0.81-0.91 (m, 1H), 0.67-0.77 (m, 1H).

Step 6—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-cyanocyclopropyl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate and (R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-cyanocyclopropyl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R or S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-((1-cyanocyclopropyl)methyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Isomer 1 from Step 5, 200 mg, 0.372 mmol) in MeOH (10 ml) was added magnesium (181 mg, 7.44 mmol) in one portion at 25° C. under nitrogen. The reaction was stirred at 25° C. for 18 hours, then quenched with saturated NH₄Cl solution (80 mL) and extracted with EtOAc (3×70 mL). The organic layers were combined, dried over Na₂SO₄, filtered and the filtrate concentrated in vacuum. The crude product was purified by pre-TLC (petroleum. ether/EtOAc=3:1) to afford the title compound (Isomer 1 from Step 6) as a white solid.

The other enantiomer (Isomer 2 from Step 6) was prepared using a similar procedure starting with Isomer 2 from Step 5. Both enantiomers have the same analytical data: LCMS (ESI) calculated for C₁₈H₂₁F₃N₃O₃ [M+H]⁺: 384.1. found: 384.2.

Step 7—Preparation of (R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((1-cyanocyclopropyl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate and (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((1-cyanocyclopropyl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R or S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-cyanocyclopropyl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Isomer 1 from Step 6, 40 mg, 0.104 mmol) in pyridine (2 mL) and THF (2 mL) was added 3-chloro-1-ethyl-1H-pyrazole-4-sulfonyl chloride (47.8 mg, 0.209 mmol). The reaction was stirred at 25° C. for 18 h, then concentrated. The title compound (Isomer 1 of Step 7, Example 93A) was obtained by prep-HPLC as a white solid.

The other enantiomer, Example 93B, was prepared using a similar procedure from Isomer 2 from Step 6. Both enantiomers have the same analytical data: LCMS (ESI) calculated for C₂₃H₂₆ClF₃N₅O₅S [M+H]⁺: 576.1. found: 576.1; ¹H-NMR (CDCl₃, 400 MHz) δ 8.08 (1H, s), 7.81 (1H, s), 6.77-6.82 (2H, m), 6.59 (1H, s), 4.27-4.31 (1H, m,), 4.21-4.22 (1H, m), 4.01-4.07 (2H, m), 3.40-3.45 (1H, m), 2.01-2.02 (2H, m), 1.69 (6H, s), 1.39-1.43 (3H, m), 1.23-1.27 (2H, m), 0.91-0.93 (1H, m), 0.81-0.83 (2H, m).

Example 94 Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-cyano-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate and (R)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-cyano-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Examples 94A and 94B)

Step 1—Preparation of (R and S)-2,2-dimethyl-3-(oxiran-2-yl)propanenitrile

To a solution of isobutyronitrile (5 g, 72.4 mmol) in THF (10 mL) was added LDA (36.2 mL, 72.4 mmol) dropwise at −78° C. under nitrogen. After 1 h, the reaction mixture was added dropwise to a solution of 2-(bromomethyl)oxirane (9.91 g, 72.4 mmol) in THF (4 mL) at −78° C. The resulting reaction was stirred at −78° C. for 3 h, then quenched with saturated NH₄Cl solution (20 mL) and diluted with water (100 mL). The aqueous layer was extracted with DCM (40 mL×3) and the combined organic layers were washed with brine (40 mL×2), dried over Na₂SO₄ and evaporated to dryness. The crude product was purified by silica gel chromatography eluted with petroleum ether:EtOAc=50:1 to 40:1 to afford the title product as yellow oil. ¹H NMR (CDCl₃, 400 MHz) δ 3.05-3.14 (m, 1H), 2.80 (d, J=4.3 Hz, 1H), 2.45-2.53 (m, 1H), 1.81-1.90 (m, 1H), 1.59-1.64 (m, 1H), 1.44 (s, 3H), 1.40 (s, 3H).

Step 2—Preparation of (R and S)-2,2-dimethyl-3-(6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanenitrile

To a mixture of N-(2-fluoro-5-nitrophenyl)-4-methylbenzenesulfonamide (5 g, 16.11 mmol) and (R and S)-2,2-dimethyl-3-(oxiran-2-yl)propanenitrile (5.04 g, 40.3 mmol) in DMF (50 mL) was added K₂CO₃ (6.68 g, 48.3 mmol) in one portion at room temperature under nitrogen. The resulting mixture was stirred at 100° C. for 4 days, then diluted with water (200 mL) and extracted with EtOAc (50 mL×4). The combined organic layers were washed with brine (50 mL×2), dried over Na₂SO₄, filtered and evaporated to dryness. The crude product was purified by silica gel column (petroleum ether:EtOAc=20:1 to 3:1) to afford the title product as a yellow oil. LCMS (ESI) calculated for C₂₀H₂₂N₃O₅S [M+H]⁺: 416. found: 416. ¹H NMR (CDCl₃, 400 MHz) δ 8.72 (d, J=2.4 Hz, 1H), 7.93 (dd, J=2.4, 9.0 Hz, 1H), 7.60 (d, J=8.2 Hz, 2H), 7.29 (d, J=8.2 Hz, 2H), 6.91 (d, J=9.0 Hz, 1H), 5.27 (s, 2H), 4.24 (dd, J=2.2, 14.3 Hz, 1H), 3.78-3.87 (m, 1H), 3.26 (dd, J=9.2, 14.3 Hz, 1H), 2.38 (s, 3H), 1.78-1.86 (m, 1H), 1.68-1.75 (m, 1H), 1.38 (s, 3H), 1.35 (s, 3H).

Step 3—Preparation of (R and S)-3-(6-amino-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2,2-dimethylpropanenitrile

To a solution of (R and S)-2,2-dimethyl-3-(6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanenitrile (4.6 g, 11.07 mmol) in EtOAc (50 mL) were added di-tert-butyl dicarbonate (3.62 g, 16.61 mmol) and Pd/C (0.46 g) at room temperature under nitrogen. The mixture was stirred at 25° C. overnight under H₂ (50 psi), then filtered over CELITE and evaporated to dryness. The crude product was purified by silica gel chromatography eluting with petroleum ether:EtOAc=5:1 to afford the title product as a yellow solid. LCMS (ESI) calculated for C₂₅H₃₂N₃O₅S [M+H]⁺: 486. found: 486. ¹H NMR (CDCl₃, 400 MHz) δ 7.64 (d, J=1.9 Hz, 1H), 7.55 (d, J=8.2 Hz, 2H), 7.25 (br s, 2H), 6.73 (d, J=8.6 Hz, 1H), 6.40 (br s, 1H), 4.15 (dd, J=1.7, 14.2 Hz, 1H), 3.56 (t, J=8.8 Hz, 1H), 3.18 (dd, J=9.6, 14.2 Hz, 1H), 2.36 (s, 3H), 1.67-1.76 (m, 1H), 1.62 (dd, J=2.3, 14.8 Hz, 1H), 1.50 (s, 9H), 1.33 (s, 3H), 1.31 (s, 3H).

Step 4—Preparation of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyano-2-methyl propyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A solution of (R and S)-tert-butyl (2-(2-cyano-2-methylpropyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (5.0 g, 10.38 mmol) in HCl in dioxane (4 M, 100 mL) was stirred at 25° C. for 1 h. The reaction solution was evaporated to dryness to give the crude (R and S)-3-(6-amino-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2,2-dimethylpropanenitrile as brown oil. The crude product was used directly in the next step without further purification.

To a solution of the above product (4.0 g, 10.38 mmol) in DMSO (40 mL) was added 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (2.42 g, 10.90 mmol) in one portion at room temperature under nitrogen. The mixture was stirred at 80° C. for 4 h, then diluted with water (50 mL) and extracted with EtOAc (25 mL×3). The combined organic layers were washed with brine, dried over Na₂SO₄ and evaporated to dryness. The crude product was purified by prep-TLC (petroleum ether:EtOAc=3:1) to afford the title as a yellow oil. LCMS (ESI) calculated for C₂₅H₂₉F₃N₃O₅S [M+H]⁺: 540. found: 540. ¹H NMR (CDCl₃, 400 MHz) δ 7.73 (brs, 1H), 7.56 (d, J=8.2 Hz, 2H), 7.24 (s, 3H), 6.76 (d, J=8.6 Hz, 1H), 6.61 (brs, 1H), 4.15 (dd, J=2.0, 14.1 Hz, 1H), 3.58 (t, J=8.6 Hz, 1H), 3.19 (dd, J=9.4, 14.1 Hz, 1H), 2.37 (s, 3H), 1.75 (s, 6H), 1.69-1.73 (m, 1H), 1.64 (d, J=2.4 Hz, 1H), 1.34 (s, 3H), 1.31 (s, 3H).

Step 5—Preparation of (S)-3,3-difluoro-2-methylbutan-2-yl(2-(2-cyano-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate and (R)-3,3-difluoro-2-methylbutan-2-yl (2-(2-cyano-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyano-2-methylpropyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (4.5 g, 8.34 mmol) in MeOH (60 ml) was added magnesium (2.0 g, 83 mmol) in one portion at room temperature under nitrogen. The mixture was stirred at 80° C. for 4 h, then diluted with MeOH (100 mL) and filtered. The resulting filtrate was evaporated to dryness and the crude product purified by silica gel column (petroleum ether:EtOAc=15:1 to 2:1) to afford the product of the title racemate as a yellow oil.

The two enantiomers were separated by SFC method (column: Chiralpak AD-H 250×4.6 mm I.D., Sum; Mobile phase: ethanol (0.05% DEA) in CO₂ from 5% to 40%; Flow rate: 2.35 mL/min wavelength: 220 nm). Isomer 1 RT=6.853 min and Isomer 2 RT=7.966 min. Both enantiomers have the same analytical data: LCMS (ESI) calculated for C₁₈H₂₃F₃N₃O₃ [M+H]⁺: 386. found: 386. ¹H NMR (CDCl₃, 400 MHz) δ 6.81 (brs, 1H), 6.68 (d, J=8.6 Hz, 1H), 6.51 (br s, 1H), 6.42 (d, J=8.2 Hz, 1H), 4.34 (t, J=7.0 Hz, 1H), 3.39 (d, J=11.7 Hz, 1H), 3.13 (dd, J=6.9, 11.5 Hz, 1H), 1.91 (dd, J=8.8, 14.7 Hz, 1H), 1.73-1.78 (m, 1H), 1.71 (s, 6H), 1.47 (s, 3H), 1.41 (s, 3H).

Step 6—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-cyano-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate and (R)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-cyano-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R or S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyano-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Isomer 1 from Step 5; 60 mg, 0.156 mmol, isomer 1) in THF (2 mL) were added pyridine (0.5 ml, 6.18 mmol) and 3-chloro-1-ethyl-1H-pyrazole-4-sulfonyl chloride (150 mg, 0.655 mmol) in one portion at room temperature under nitrogen. The reaction was stirred at 60° C. overnight, then evaporated to dryness. The crude product was purified by prep-TLC (petroleum ether:EtOAc=2:1) to afford the title compound (Example 94A) as a yellow oil.

The other enantiomer, (Example 94B) was prepared using a similar procedure as described above starting with Isomer 2 from Step 5. Both enantiomers have the same analytical data: LCMS (ESI) calculated for C₂₃H₂₈ClF₃N₅O₅S [M+H]⁺: 578. found: 578. ¹H NMR (CDCl₃, 400 MHz) δ 8.12 (brs, 1H), 7.85 (brs, 1H), 6.78-6.87 (m, 2H), 6.75 (brs, 1H), 4.18-4.31 (m, 2H), 4.07 (q, J=7.2 Hz, 2H), 3.45 (dd, J=8.4, 12.7 Hz, 1H), 1.88 (d, J=8.6 Hz, 1H), 1.78 (brs, 1H), 1.72 (br s, 6H), 1.40-1.47 (m, 9H).

Example 95 Preparation of Additional Gem-Dimethyl Propionic Nitriles

The compounds in Table 28 below were prepared based on the experimental procedures described in Example 94 and elsewhere in the detailed description, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 28 Ex. Observed No. Structure Name m/z 95A

(R)-1,1,1-trifluoro-2- methylpropan-2-yl (2-(2-cyano- 2-methylpropyl)-4-((4-fluoro-3- (trifluoromethyl)phenyl)sulfonyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 612 (M + H)+ 95B

(R)-1,1,1-trifluoro-2- methylpropan-2-yl (2-(2-cyano- 2-methylpropyl)-4-((4-fluoro-3- methoxyphenyl)sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 596 (M + Na)+ 95C

(R)-1,1,1-trifluoro-2- methylpropan-2-yl (2-(2-cyano- 2-methylpropyl)-4-((4-fluoro-3- methylphenyl)sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 558 (M + H)+ 95D

(S)-1,1,1-trifluoro-2- methylpropan-2-yl (2-(2-cyano- 2-methylpropyl)-4-((4-fluoro-3- methoxyphenyl)sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 596 (M + Na)+ 95E

(S)-1,1,1-trifluoro-2- methylpropan-2-yl (2-(2-cyano- 2-methylpropyl)-4-((4-fluoro-3- methylphenyl)sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 580 (M + Na)+ 95F

(R)-1,1,1-trifluoro-2- methylpropan-2-yl (2-(2-cyano- 2-methylpropyl)-4-((3-ethoxy- 1-ethyl-1H-pyrazol-4- yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 588 (M + H)+ 95G

(S)-1,1,1-trifluoro-2- methylpropan-2-yl (2-(2-cyano- 2-methylpropyl)-4-((3-ethoxy- 1-ethyl-1H-pyrazol-4- yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 588 (M + H)+

Example 96 Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(3-(cyclopropanesulfonamido)-3-oxopropyl)-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Example 96)

To a solution of (S)-3-(4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoic acid (50 mg, 0.82 mmol) in DCM (1 mL) was added EDCI (32 mg, 0.17 mmol) and DMAP (20 mg, 0.17 mmol) at 0° C. The reaction was stirred at room temperature for 1 h, then cyclopropanesulfonamide (23 mg, 0.17 mmol) and DIPEA (21 mg, 0.17 mmol) were added. After stirring for 12 h at room temperature, the reaction mixture was diluted with water and 1N HCl, then extracted 3× with EtOAc. The combined organic layers were washed with water, brine, dried over Na₂SO₄ and concentrated in vacuo. The crude product was purified by prep-HPLC (MeCN/water using TFA buffer) to give the title compound as a colorless oil. LCMS (ESI) calculated for C₂₆H₂₇F₇N₃O₈S₂ [M+H]⁺: 706. found: 706. ¹H-NMR (CDCl₃, 400 MHz) δ 8.28 (1H, s), 8.09 (1H, d, J=4.4 Hz), 7.99 (1H, s), 7.86 (1H, s), 7.33-7.38 (1H, m), 6.97 (1H, dd, J=2.0, 8.8 Hz), 6.78 (1H, d, J=9.2 Hz), 6.65 (1H, brs), 4.29 (1H, d, J=14.0 Hz), 3.73-3.75 (1H, m), 3.24 (1H, dd, J=9.6, 13.6 Hz), 2.87-2.95 (1H, m), 2.49-2.60 (2H, m), 1.97-2.07 (1H, m), 1.80-1.87 (1H, m), 1.76 (6H, s), 1.36-1.38 (2H, m), 1.10-1.12 (2H, m).

Example 97 Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl ((S)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((S)-3-(cyclopropanesulfonamido)-2-methyl-3-oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate and 1,1,1-trifluoro-2-methylpropan-2-yl ((S)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((R)-3-(cyclopropanesulfonamido)-2-methyl-3-oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Examples 97A and 97B)

A mixture of (S or R)-3-((S)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanoic acid (50 mg, 0.086 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridine-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (48.9 mg, 0.129 mmol) and N-ethyl-N-isopropylpropan-2-amine (33.3 mg, 0.257 mmol) in anhydrous DMF (0.5 mL) was stirred at 20° C. for 20 minutes, followed by the addition of cyclopropanesulfonamide (31.2 mg, 0.257 mmol). After stirring for 24 hours, 2 mL water was added to the reaction and the resulting mixture extracted with ethyl acetate (1.5 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The crude product was purified by prep-HPLC (MeCN/water using TFA buffer) to afford the title compound (Example 97A) as a white solid. LCMS (ESI) calculated for C₂₅H₃₂ClF₃N₅O₈S₂ [M+H]⁺: 686. found: 686. ¹H-NMR (CDCl₃, 400 MHz) δ 8.57 (1H, s), 8.19 (1H, s), 7.89 (1H, s), 6.86-6.92 (2H, m), 6.77 (1H, s), 4.34 (1H, dd, J=14.0, 2.0 Hz), 4.19 (2H, q, J=7.2 Hz), 4.06 (1H, br s), 3.41-3.57 (1H, m), 2.98-3.01 (1H, m), 2.78-2.80 (1H, m), 2.05-2.15 (1H, m), 1.81 (6H, s), 1.75-1.78 (1H, m), 1.55 (3H, t, J=7.6 Hz), 1.41-1.46 (1H, m), 1.27-1.37 (3H, m), 1.13-1.21 (1H, m), 1.02-1.08 (1H, m)

The other diastereomer (Example 97B) was prepared using a similar procedure as described above. LCMS (ESI) calculated for C₂₅H₃₂ClF₃N₅O₈S₂ [M+H]⁺: 686. found: 686. ¹H-NMR (CDCl₃, 400 MHz) δ 8.56 (1H, s), 8.12 (1H, s), 7.82 (1H, s), 6.81-6.84 (2H, m), 6.69 (1H, s), 4.37 (1H, d, J=13.6 Hz), 4.01-4.11 (4H, m), 3.26-3.30 (1H, m), 2.93-2.96 (1H, m), 2.65-2.67 (1H, m), 2.02-2.09 (1H, m), 1.73 (6H, s), 1.44 (3H, t, J=7.2 Hz), 1.32-1.40 (2H, m), 1.25 (3H, d, J=6.8 Hz), 1.11 (2H, d, J=8.0 Hz).

Example 98 Preparation of Additional Propionic Sulfonylamides of Benzoxazines

The compounds in Table 29 below were prepared based on the experimental procedures described in Examples 96 and 97 and elsewhere in the detailed description, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 29 Ex. Observed No. Structure Name m/z 98A

2,2,2-trifluoro-1,1-dimethylethyl [(2S)- 2-{3-[(tert-butylsulfonyl)amino]-3- oxopropyl}-4-{[4-fluoro-3- (trifluoromethyl)phenyl]sulfonyl}-3,4- dihydro-2H-1,4-benzoxazin-6- yl]carbamate 722 (M + H)+ 98B

2,2,2-trifluoro-1,1-dimethylethyl [(2S)- 4-{[4-fluoro-3- (trifluoromethyl)phenyl]sulfonyl}-2-(3- {[(4-methylphenyl)sulfonyl]amino}-3- oxopropyl)-3,4-dihydro-2H-1,4- benzoxazin-6-yl]carbamate 756 (M + H)+ 98C

2,2,2-trifluoro-1,1-dimethylethyl [(2S)- 4-{[4-fluoro-3- (trifluoromethyl)phenyl]sulfonyl}-2-(3- oxo-3-{[(trifluoro- methyl)sulfonyl]amino}propyl)- 3,4-dihydro-2H-1,4-benzoxazin-6- yl]carbamate 734 (M + H)+ 98D

1,1,1-trifluoro-2-methylpropan-2-yl ((S)-2-((R and S)-3- (cyclopropanesulfonamido)-2-methyl- 3-oxopropyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 724 (M + Na)+ 98E

1,1,1-trifluoro-2-methylpropan-2-yl ((S)-4-((3-chloro-1-ethyl-1H-pyrazol-4- yl)sulfonyl)-2-((R or S)-3-(1,1- dimethylethylsulfonamido)-2-methyl-3- oxopropyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 702 (M + H)+ 98F

1,1,1-trifluoro-2-methylpropan-2-yl ((S)-2-((R or S)-3- (cyclopropanesulfonamido)-2-methyl- 3-oxopropyl)-4-((4-fluoro-3- methoxyphenyl)sulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6- yl)carbamate 704 (M + Na)+ 98G

1,1,1-trifluoro-2-methylpropan-2-yl ((S)-2-((R or S)-3-(1,1- dimethylethylsulfonamido)-2-methyl-3- oxopropyl)-4-((4-fluoro-3- methoxyphenyl)sulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6- yl)carbamate 698 (M + H)+ 98H

1,1,1-trifluoro-2-methylpropan-2-yl ((S)-2-((R or S)-3- (cyclopropanesulfonamido)-2-methyl- 3-oxopropyl)-4-((4-fluoro-3- methoxyphenyl)sulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6- yl)carbamate 704 (M + Na)+ 98i

1,1,1-trifluoro-2-methylpropan-2-yl ((S)-2-((R or S)-3-(1,1- dimethylethylsulfonamido)-2-methyl-3- oxopropyl)-4-((4-fluoro-3- methoxyphenyl)sulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6- yl)carbamate 696 (M − H)− 98J

1,1,1-trifluoro-2-methylpropan-2-yl ((S)-4-((3-chloro-1-ethyl-1H-pyrazol-4- yl)sulfonyl)-2-((R or S)-3-(1,1- dimethylethylsulfonamido)-2-methyl-3- oxopropyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 702 (M + H)+

Example 99 Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-2-(oxetan-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Example 99)

Step 1—Preparation of (S)-2-((4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)propane-1,3-diol

To a solution of (S)-diethyl 2-((4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)malonate (700 mg, 1.58 mmol) in MeOH (20 mL) was added NaBH₄ (1.00 g, 26.4 mmol) in portions and the resulting mixture was stirred at 20° C. for 6 h. The reaction was quenched with H₂O, extracted with EtOAc (3×50 mL), washed with H₂O and brine and dried over Na₂SO₄. The combined organic layers were concentrated in vacuo and purified by flash column chromatography (0-60% ethyl acetate in petroleum ether) to afford the title compound as yellow oil. LCMS (ESI) calculated for C₁₉H₂₃N₂O₅ [M+H]⁺: 359.2. found: 359.1, ¹H NMR (400 MHz, CDCl₃) δ 7.47-7.56 (m, 2H), 7.21-7.33 (m, 3H), 7.19 (s, 2H), 6.76 (d, J=8.2 Hz, 1H), 4.39-4.49 (m, 2H), 4.23 4.33 (m, 1H), 3.65-3.86 (m, 4H), 3.20-3.31 (m, 1H), 3.04-3.16 (m, 1H), 1.69-1.80 (m, 3H).

Step 2—Preparation of 3-((S)-4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-(hydroxymethyl)propyl 4-methylbenzenesulfonate

To a solution of (S)-2-((4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)propane-1,3-diol (500 mg, 1.40 mmol) in 20 mL of THF was added butyllithium (1.0 mL, 1.4 mmol) at −70° C. under N₂ and the reaction was stirred at −70° C. for 1 h, then treated with 4-methylbenzene-1-sulfonyl chloride (300 mg, 1.57 mmol) in 5 mL of THF. After 1 h at −70° C., the reaction was slowly warmed to room temperature and stirred for an additional 2 h. The reaction mixture was then quenched with aq. NH₄Cl, extracted with EtOAc (3×50 mL) and the combined organic layer was concentrated in vacuo. The crude product was purified by flash column chromatography (0-70% ethyl acetate in petroleum ether) to afford the title compound as yellow oil. LCMS (ESI) calculated for C₂₆H₂₉N₂O₇S [M+H]⁺: 513.2. found: 513.2, ¹H NMR (400 MHz, CDCl₃) δ 7.71 (dd, J=8.0 Hz, 2.5 Hz, 2H), 7.43-7.54 (m, 2H), 7.13-7.34 (m, 7H), 6.69 (t, J=8.8 Hz, 1H), 4.36-4.48 (m, 2H), 4.01-4.26 (m, 3H), 3.54-3.71 (m, 2H), 3.22 (d, J=12.1 Hz, 1H), 2.99 3.10 (m, 1H), 2.37 (d, J=2.7 Hz, 3H), 2.16 (d, J=5.5 Hz, 1H), 1.56-1.67 (m, 2H).

Step 3—Preparation of (S)-4-benzyl-6-nitro-2-(oxetan-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a solution of 3-((S)-4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-(hydroxymethyl)propyl 4-methylbenzenesulfonate (650 mg, 1.27 mmol) in 20 mL of THF was added sodium hydride (60%, 152 mg, 3.80 mmol) at 0° C. The reaction was stirred at room temperature for 20 h, then quenched with aq.NH₄Cl and extracted with EtOAc (3×20 mL). The combined organic layer was concentrated in vacuo and the crude product was purified by flash column chromatography (0-50% ethyl acetate in petroleum ether) to afford the title compound as yellow oil. LCMS (ESI) calculated for C₁₉H₂₁N₂O₄ [M+H]⁺: 341.1. found: 341.1, ¹H NMR (400 MHz, CDCl₃) δ 7.35-7.51 (m, 2H), 7.10-7.25 (m, 5H), 6.63 (d, J=8.6 Hz, 1H), 4.61-4.74 (m, 2H), 4.21-4.41 (m, 4H), 4.00 (brs, 1H), 3.06-3.20 (m, 2H), 2.97 (dd, J=12.1 Hz, 7.8 Hz, 1H), 1.89-2.00 (m, 1H), 1.85-1.74 (m, 1H).

Step 4—Preparation of (S)-2-(oxetan-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine

To a solution of (S)-4-benzyl-6-nitro-2-(oxetan-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (400 mg, 1.18 mmol) in 20 mL of MeOH was added 10% Pd/C (300 mg, 2.82 mmol), the reaction was stirred under H₂ (50 psi) for 4 h. The reaction mixture was then filtered and concentrated in vacuo to afford the title compound as brown oil. LCMS (ESI) calculated for C₁₂H₁₇N₂O₂ [M+H]⁺: 221.1. found: 221.1.

Step 5—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(oxetan-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-2-(oxetan-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine (250 mg, 1.14 mmol) in DMSO (5 mL) was added 3-methyl-1-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-1H-imidazol-3-ium iodide (413 mg, 1.14 mmol). The resulting mixture was stirred at room temperature for 0.5 h, then quenched with NH₄Cl (aq) and extracted with EtOAc (3×20 mL). The combined organic layer was concentrated in vacuo and the crude product was purified by flash column chromatography (0-40% ethyl acetate in petroleum ether) to afford the title compound as yellow oil. LCMS (ESI) calculated for C₁₇H₂₂F₃N₂O₄ [M+H]⁺: 375.1. found: 375.1, ¹H NMR (400 MHz, DMSO) δ 9.38 (br s, 1H), 6.81 (br s, 1H), 6.50 (s, 2H), 5.85 (br s, 1H), 4.59-4.75 (m, 2H), 4.33 (q, J=6.0 Hz, 2H), 3.89 (d, J=7.0 Hz, 1H), 3.16-3.26 (m, 2H), 2.87-2.96 (m, 1H), 1.88-2.03 (m, 2H), 1.69 (s, 6H).

Step 6—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-2-(oxetan-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(oxetan-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (30 mg, 0.080 mmol) in THF (4 mL) and pyridine (0.5 mL) was added 4-fluoro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (50 mg, 0.190 mmol). The resulting mixture was stirred at 50° C. for 6 h, then quenched with 10 mL of water and extracted with EtOAc (3×10 mL). The combined organic layers were concentrated in vacuo and the crude product was purified by prep-HPLC to afford the title compound as a white solid. LCMS (ESI) calculated for C₂₄H₂₄F₇N₂O₆S [M+H]⁺: 601.1. found: 601.1, ¹H NMR (400 MHz, MeOD) 8.18 (d, J=7.4 Hz, 2H), 8.03 (br s, 1H), 7.53-7.59 (m, 1H), 6.97 (dd, J=8.8 Hz, 2.2 Hz, 1H), 6.71 (d, J=9.0 Hz, 1H), 4.79 (d, J=5.9 Hz, 2H), 4.45 (dd, J=11.3 Hz, 5.5 Hz, 2H), 4.32-4.37 (m, 1H), 3.62 (brs, 1H), 3.35-3.39 (m, 1H), 3.23-3.29 (m, 1H), 1.95-2.05 (m, 2H), 1.77 (s, 6H).

Example 100 Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Example 100)

Step 1—Preparation of (S)-ethyl 3-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate

To a solution of (S)-diethyl 2-((4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)malonate (5 g, 11.30 mmol) in DMSO (50 mL) was added lithium chloride (2.395 g, 56.5 mmol). The reaction was stirred at 170° C. for 10 hours, then cooled to room temperature and diluted with ethyl acetate (200 mL) and washed with water (3×100 mL). The separated organic layers were dried with Na₂SO₄ and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (petroleum ether:ethyl acetate=10:1 to 5:1 to 3:1) to give the titled compound as orange oil. LCMS (ESI) calculated for C₂₀H₂₃N₂O₅ [M+H]⁺: 371.1. found: 371.0.

Step 2—Preparation of (S)-3-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoic acid

To a solution of ethyl 3-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate (500 mg, 1.350 mmol) in dioxane (5 mL) and water (3 mL) was added lithium hydroxide (48.5 mg, 2.025 mmol). The reaction was stirred at 20° C. for 4 hours, then diluted with water (10 mL) and extracted with ethyl acetate (3×5 mL). The aqueous layer was acidified with hydrochloric acid (1M, 10 mL) to pH=3 and extracted with ethyl acetate (10 mL×3). The combined organic layers were dried (Na₂SO₄), filtered and concentrated under reduced pressure to give the titled compound as orange oil. LCMS (ESI) calculated for C₁₈H₁₉N₂O₅ [M+H]⁺: 343.1. found: 343.1; ¹H-NMR (CDCl₃, 400 MHz) δ 7.52 (2H, s), 7.24-7.31 (5H, m), 6.77-6.79 (1H, m), 4.44 (2H, s), 4.22-4.24 (1H, m), 3.26-3.29 (1H, m), 3.08-3.13 (1H, m), 2.58 (2H, s), 1.91-1.93 (2H, m).

Step 3—Preparation of (S)-2-(3-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoyl)hydrazinecarboxamide

To a solution of (S)-3-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoic acid (500 mg, 1.461 mmol) in deimethyl formamide (0.1 mL) and toluene (5 ml) was added oxalyl dichloride (1.1 g, 8.76 mmol) dropwise. The reaction was stirred at 20° C. for 10 minutes, then heated to 80° C. and stirred at this temperature for 1 hour. After cooling to 20° C., the reaction mixture was concentrated under reduced pressure. To a solution of hydrazinecarboxamide (121 mg, 1.607 mmol) in tetrahydrofuran (10 mL) and water (2 mL) was added sodium hydroxide (117 mg, 2.92 mmol), followed by the slow addition of the crude product in tetrahydrofuran (10 mL) described above. The reaction was stirred at 0° C. for 2 hours, then concentrated to give the title compound as a red oil, which was used in the next step without further purification. LCMS (ESI) calculated for C₁₉H₂₂N₅O₅ [M+H]⁺: 400.1. found: 400.1.

Step 4—Preparation of (S)-3-(2-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1H-1,2,4-triazol-5(4H)-one

A solution of (S)-2-(3-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoyl)hydrazinecarboxamide (590 mg, 1.344 mmol) in 2M sodium hydroxide (20 mL), was stirred at 100° C. for 12 hours, then cooled to 20° C. and acidified with 1M hydrochloric acid to pH=2. The resulting mixture was filtered and concentrated to give the title compound as an orange solid. LCMS (ESI) calculated for C₁₉H₂₀N₅O₄ [M+H]⁺: 382.1. found: 382.1. ¹H-NMR (CDCl₃, 400 MHz) δ 7.51 (2H, s), 7.23-7.31 (5H, m), 6.76-6.78 (1H, m), 4.43 (2H, s), 4.23 (1H, s), 3.13-3.29 (1H, m), 3.09-3.12 (1H, m), 2.71-2.76 (1H, m), 2.54-2.56 (1H, m), 1.90-1.98 (1H, m).

Step 5—Preparation of (S)-3-(2-(6-amino-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1H-1,2,4-triazol-5(4H)-one

To a solution of (S)-3-(2-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1H-1,2,4-triazol-5(4H)-one (40 mg, 0.105 mmol) in methanol (15 mL) was added Pd(OH)₂ under argon. The mixture was degassed under hydrogen several times, and stirred at 20° C. under H₂ balloon for 15 hours. The reaction was filtered and concentrated under reduced pressure to give the title compound as a dark oil. LCMS (ESI) calculated for C₁₂H₁₆N₅O₂ [M+H]⁺: 262.1. found: 262.2.

Step 6—Preparation of (S)-4-(2,6-difluorobenzyl)-1-(4-fluorophenyl)-N—((R)-1-phenylethyl)piperazine-2-carboxamide

To a solution of (S)-3-(2-(6-amino-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1H-1,2,4-triazol-5(4H)-one (20 mg, 0.077 mmol) in DMSO (3 mL) was added 3-methyl-1-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-1H-imidazol-3-ium iodide (21.79 mg, 0.092 mmol) and the reaction was stirred at 20° C. for 20 minutes. The reaction mixture was directly purified by prep-HPLC (MeCN/H₂O as eluent, 0.05% TFA) to give the title compound as a white solid. LCMS (ESI) calculated for C₁₇H₂₁F₃N₅O₄ [M+H]⁺: 416.1. found: 416.1.

Step 7—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (10 mg, 0.024 mmol) in tetrahydrofuran (5 mL) was added pyridine (1 mL) and 3-chloro-1-ethyl-1H-pyrazole-4-sulfonyl chloride (16.5 mg, 0.072 mmol). The reaction was stirred at 15° C. for 3 hours, then directly purified by pre-HPLC (MeCN/H₂O as eluent, 0.05% TFA) to give the title compound as a white solid. LCMS (ESI) calculated for C₂₂H₂₆ClF₃N₇O₆S [M+H]⁺: 608.1. found: 608.0; ¹H-NMR (CDCl₃, 400 MHz) δ 8.27 (1H, s), 7.89 (1H, s), 6.92-6.95 (1H, m), 6.74-6.77 (1H, m), 4.34-4.37 (1H, m,), 4.07-4.11 (2H, m), 3.89 (2H, s), 3.34-3.38 (1H, m), 2.69-2.74 (2H, m), 1.92-2.01 (3H, m),1.74 (6H, s), 1.36-1.40 (3H, m).

Example 101 Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Example 101)

To a solution of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (30 mg, 0.049 mmol) in DMF (2 mL) was added potassium carbonate (6.82 mg, 0.049 mmol) and iodomethane (7.00 mg, 0.049 mmol) at 0° C. The reaction was stirred at 25° C. for 2 hours, then concentrated and purified by pre-HPLC (MeCN/H₂O as eluent, 0.05% TFA) to afford the title compound as a yellow solid. LCMS (ESI) calculated for C₂₃H₂₈ClF₃N₇O₆S [M+H]⁺: 622.1. found: 622.1; ¹H-NMR (CDCl₃, 400 MHz) δ 8.11 (1H, s), 7.85 (1H, s), 6.88 (2H, s), 6.77-6.79 (1H, m), 4.38 (1H, d, J=13.2 Hz), 4.08-4.10 (2H, m,), 3.64 (1H, s), 3.38-3.43 (1H, m), 3.23 (3H, s), 2.70-2.76 (2H, m), 2.00-2.04 (2H, m), 1.74 (6H, s), 1.43-1.47 (3H, m).

Example 102 Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Example 102)

Step 1—Preparation of (S)-3-(6-amino-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanenitrile

A mixture of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyanoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (see Example 92; 100 mg, 0.18 mmol), LiOH.H₂O (84 mg, 2 mmol), dioxane (1 mL) and H₂O (1 mL) were stirred at 40° C. for 6 hours. The reaction mixture was extracted with EtOAc, dried over Na₂SO₄ and concentrated in vacuo to give the crude title product as a white solid, which was used in the next step without further purification. LCMS (ESI) calculated for C₁₈H₁₇F₃N₃O₃S [M+H]⁺: 412. found: 412.

Step 2—Preparation of (S)-tert-butyl (2-(2-cyanoethyl)-4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A mixture of (S)-3-(6-amino-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanenitrile (100 mg, 0.24 mmol), Boc₂O (218 mg, 1 mmol), Et₃N (202 mg, 2 mmol) and DCM (10 mL) were stirred at 15° C. for 16 hours. The reaction mixture was extracted with DCM and water and the organic layer washed with brine, dried over Na₂SO₄ and concentrated in vacuo. The crude product was purified by prep-TLC to give the title compound as a yellow solid. LCMS (ESI) calculated for C₂₃H₂₅F₃N₃O₅S [M+H]⁺: 512. found: 512.

Step 3—Preparation of (S,Z)-tert-butyl(2-(3-amino-3-(hydroxyimino)propyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A mixture of (S)-tert-butyl (2-(2-cyanoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (20 mg, 0.04 mmol), hydroxylamine hydrochloride (138 mg, 2 mmol), K₂CO₃ (1.38 g, 10 mmol) and MeOH (10 mL) was stirred at 60° C. for 18 hours. The reaction mixture was concentrated in vacuo and extracted with water and EtOAc. The organic phase was washed with brine, dried over Na₂SO₄ and concentrated. The crude product was purified by prep-TLC to give the title compound as a white solid. LCMS (ESI) calculated for C₂₃H₂₈F₃N₄O₆S [M+H]⁺: 545. found: 545. ¹H NMR (CDCl₃, 400 MHz) δ 7.94 (br s, 1H), 7.85 (d, J=7.43 Hz, 1H), 7.75 (d, J=7.4 Hz, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.53-7.60 (m, 1H), 7.00-7.12 (m, 1H), 6.64-6.71 (m, 1H), 6.42 (br s, 1H), 4.60 (br s, 1H), 4.20 (d, J=14.1 Hz, 1H), 3.43 (br s, 1H), 3.13 (dd, J=9.8, 13.69 Hz, 1H), 2.15-2.32 (m, 2H), 1.68-1.78 (m, 2H), 1.40-1.50 (m, 9H).

Step 4—Preparation of (S)-tert-butyl (2-(2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A solution of (S,Z)-tert-butyl (2-(3-amino-3-(hydroxyimino)propyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (20 mg, 0.04 mmol) in MeCN (5 mL) was added pyridine (0.5 mL) and triphosgene (6 mg, 0.02 mmol). After stirred for 18 hours at 15° C., the reaction mixture was concentrated in vacuo and extracted with EtOAc and water. The organic phase was washed with brine, dried over Na₂SO₄ and concentrated. The crude product was purified by prep-TLC (EtOAc) to give the title compound as yellow oil. LCMS (ESI) calculated for C₂₄H₂₆F₃N₄O₇S [M+H]⁺: 571. found: 571. ¹H NMR (CDCl₃, 400 MHz) δ 9.52 (br s, 1H), 7.95 (br s, 1H), 7.76-7.89 (m, 2H), 7.71 (d, J=2.0 Hz, 1H), 7.54-7.63 (m, 1H), 7.03 (d, J=7.8 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H), 6.40 (br s, 1H), 4.02 (d, J=6.7 Hz, 1H), 3.50-3.60 (m, 1H), 3.22 (dd, J=9.2, 13.9 Hz, 1H), 2.60-2.74 (m, 2H), 1.82-1.93 (m, 2H), 1.18 (s, 9H).

Step 5—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A solution of (S)-tert-butyl (2-(2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (57 mg, 0.1 mmol) in DCM (2 mL) was added TFA (1 mL). After stirred for 1 hour at 15° C., the reaction mixture was concentrated in vacuo. The aniline intermediate was next added to a solution of 3-methyl-1-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-1H-imidazol-3-ium iodide (73 mg, 0.2 mmol) in DMSO (2 mL). The reaction was stirred for 1 h and the mixture was directly purified with prep-HPLC (MeCN/water using TFA buffer) to give the title product as white solid. LCMS (ESI) calculated for C₂₄H₂₃F₆N₄O₇S [M+H]⁺: 625. found: 625. ¹H NMR (CD₃OD, 400 MHz) δ 8.02-8.24 (m, 3H), 7.97 (d, J=7.5 Hz, 1H), 7.77 (t, J=8.0 Hz, 1H), 7.03 (d, J=11.0 Hz, 1H), 6.74 (d, J=8.5 Hz, 1H), 4.41 (d, J=14.0 Hz, 1H), 3.58 (brs, 1H),2.69-2.78 (m, 2H), 1.89-2.06 (m, 2H), 1.79 (s, 6H).

Example 103 Preparation of (R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate and (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Examples 103A and 103B)

Step 1—Preparation of (R and S)—N-hydroxy-2,2-dimethyl-3-(6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanimidamide

To a stirred mixture of (R and S)-2,2-dimethyl-3-(6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanenitrile (see Example 94; 3.0 g, 7.22 mmol) in EtOH (30 mL) was added NH₂OH.HCl (1.0 g, 14.39 mmol), K₂CO₃ (3.0 g, 21.71 mmol) and water (10 mL). The reaction was heated to reflux for 18 hours, then cooled to room temperature and stirred for 30 minutes. The solid was filtered off and dried under vacuum to afford N-hydroxy-2,2-dimethyl-3-(6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanimidamide as a white solid.

Step 2—Preparation of (R and S)-3-(2-methyl-1-(6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propan-2-yl)-1,2,4-oxadiazol-5(2H)-one

To a stirred solution of (R and S)—N-hydroxy-2,2-dimethyl-3-(6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanimidamide (900 mg, 2.007 mmol) in DMSO (10 mL) was added CDI (488 mg, 3.01 mmol) and K₂CO₃ (555 mg, 4.01 mmol). The reaction was stirred for 18 hours at 20° C., then treated with water (10 mL) and extracted with EtOAc (15 mL). The organic layers was evaporated and the crude product purified by chromatography silica gel (petroleum ether:EtOAc=2:1 to 1:2) to afford the title compound as a light-yellow solid. LCMS (ESI) calculated for C₂₁H₂₃N₄O₇S [M+H]⁺: 475.1. found: 475.1; ¹H-NMR (CDCl₃, 400 MHz) δ 8.68 (1H, d, J=2.4 Hz), 7.85 (1H, dd, J=9.2, 2.4 Hz), 7.45 (2H, d, J=8.4 Hz), 7.22 (2H, d, J=8.0 Hz), 6.74 (1H, d, J=8.8 Hz), 4.17 (1H, dd, J=14.4, 2.0 Hz), 3.49 (1H, t, J=7.6 Hz), 3.07-3.13 (1H, m), 2.32 (3H, s), 1.82-1.86 (2H, m), 1.26 (6H, d, J=9.2 Hz).

Step 3—Preparation of (R and S)-3-(1-(6-amino-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropan-2-yl)-1,2,4-oxadiazol-5(2H)-one

To a stirred solution of (R and S)-3-(2-methyl-1-(6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propan-2-yl)-1,2,4-oxadiazol-5(2H)-one (900 mg, 1.897 mmol) in MeOH (10 mL) was added water (1 mL), Zn (124 mg, 1.897 mmol) and NH₄Cl (101 mg, 1.897 mmol). The reaction was stirred for 2 hours at 20° C., then filtered and the filtrate concentrated. The crude product was washed with EtOAc and water (20 mL each). The organic layer was concentrated to afford the title compound as a gray solid. LCMS (ESI) calculated for C₂₁H₂₅N₄O₅S [M+H]⁺: 445.1. found: 445.1.

Step 4—Preparation of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A mixture of 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (19.99 mg, 0.090 mmol), (S and R)-3-(1-(6-amino-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropan-2-yl)-1,2,4-oxadiazol-5(4H)-one (20 mg, 0.045 mmol) and concentrated HCl (one drop) in DMSO (3 mL) was stirred at 80° C. for 4 hours. Upon completion, the reaction mixture was diluted with water (10 mL), extracted with EtOAc (3×15 ml) and the combined organic layers dried and concentrated in vacuo. The crude product was purified by prep-TLC (DCM:MeOH=15:1) to give the title compound as a brown solid. LCMS (ESI) calculated for C₂₆H₃₀F₃N₄O₇S [M+H]⁺: 599.1. found: 599.1; ¹H-NMR (CDCl₃, 400 MHz) δ 7.70 (1H, s), 7.51 (2H, d, J=8.0 Hz), 7.23 (1H, s), 7.13 (1H, d, J=8.4 Hz), 6.72 (1H, s), 6.54 (1H, d, J=8.4 Hz), 4.04 (1H, d, J=12.8 Hz), 3.39-3.40 (1H, m), 3.14-3.20 (1H, m), 2.39 (3H, s), 1.81-1.83 (1H, m), 1.76 (6H, s), 1.65-1.68 (1H, m), 1.32 (3H, s), 1.23 (3H, s).

Step 5—Preparation of (R)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate and (S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A mixture of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (300 mg, 0.501 mmol) and magnesium (97 mg, 4.01 mmol) in MeOH (10 mL) was stirred at 15° C. for 36 hours. Upon completion, the reaction mixture was concentrated in vacuo, diluted with water (10 mL) and acidified with HCl (1M) to pH=2. The biphasic mixture was extracted with EtOAc (3×20 mL) and the combined organic layers dried over Na₂SO₄ and evaporated. The crude product was purified by prep-TLC to give the title racemic compound as a colorless oil.

The above racemate was resolved by SFC purification (Instrument: Thar SFC 350; Column: OD (250 mm*30 mm,10 um); Mobile phase: 30% IPA+NH₃.H₂O; 80 mL/min; Wavelength: 220 nm) to give two enantiomers (faster eluent, Isomer 1 and slower eluent, Isomer 2), which have the same analytical data: LCMS (ESI) calculated for C₁₉H₂₄F₃N₄O₅ [M+H]⁺: 445.1. found: 445.1.

Step 6—Preparation of (R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate and (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a mixture of (R or S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Isomer 1 from Step 5, 10 mg, 0.023 mmol) in THF (2 mL) was added 3-chloro-1-ethyl-1H-pyrazole-4-sulfonyl chloride (10.31 mg, 0.045 mmol) and pyridine (2 mL). The reaction mixture was stirred at 20° C. for 2 hours, then concentrated in vacuo. The crude product was purified by prep-HPLC (MeCN/water using TFA buffer) to afford the title compound (Isomer 1 from Step 6, Example 103A) as a white solid.

The other enantiomer (Isomer 2 from Step 6, Example 103B) was prepared using a similar procedure as described above from Isomer 2 from Step 5. Both enantiomers have the same analytical data: LCMS (ESI) calculated for C₂₄H₂₉ClF₃N₆O₇S [M+H]⁺: 637.1. found: 637.1; ¹H-NMR (Methanol-d4, 400 MHz) δ 8.28 (1H, s), 7.90 (1H, s), 6.91 (1H, d, J=8.8 Hz), 6.54 (1H, d, J=8.4 Hz), 4.24 (1H, d, J=14.0 Hz), 4.12 (2H, q, J=7.2 Hz), 3.97 (1H, t, J=8.4 Hz), 3.35-3.41 (1H, m), 1.96-2.02 (1H, m), 1.84-1.88 (1H, m), 1.75 (6H, s), 1.41 (3H, t, J=7.2 Hz), 1.35 (6H, s).

Example 104 Preparation of additional 1,2,4-oxadiazolones

The compounds in Table 30 below were prepared based on the experimental procedures described in Examples 102 and 103 and elsewhere in the detailed description, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 30 Ex. Observed No. Structure Name m/z 104A

2,2,2-trifluoro-1,1- dimethylethyl [(2S)-2-[2-(5- oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)ethyl]-4-{[3- (trifluoromethyl)phenyl] sulfonyl}-3,4-dihydro-2H-1,4- benzoxazin-6-yl]carbamate 625 (M + H)+ 104B

2,2,2-trifluoro-1,1- dimethylethyl {(2S)-4-[(3- cyclopropylphenyl)sulfonyl]-2- [2-(5-oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)ethyl]-3,4- dihydro-2H-1,4-benzoxazin-6- yl}carbamate 597 (M + H)+ 104C

tert-butyl {(2S)-4-[(3- cyclopropylphenyl)sulfonyl]-2- [2-(5-oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)ethyl]-3,4- dihydro-2H-1,4-benzoxazin-6- yl}carbamate 487 (M + H—tBu)+ 104D

(S)-1,1,1-trifluoro-2- methylpropan-2-yl (4-((3- chloro-1-ethyl-1H-pyrazol-4- yl)sulfonyl)-2-(2-(5-oxo-4,5- dihydro-1,2,4-oxadiazol-3- yl)ethyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 610 (M + H)+ 104E

(S)-tert-butyl (4-((3-chloro-1- ethyl-1H-pyrazol-4- yl)sulfonyl)-2-(2-(5-oxo-4,5- dihydro-1,2,4-oxadiazol-3- yl)ethyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 577 (M + Na)+ 104F

(R)-1,1,1-trifluoro-2- methylpropan-2-yl (4-((3- chloro-1-ethyl-1H-pyrazol-4- yl)sulfonyl)-2-(2-methyl-2-(5- oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)propyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 637 (M + H)+ 104G

(R)-1,1,1-trifluoro-2- methylpropan-2-yl (4-((4- fluoro-3- methoxyphenyl)sulfonyl)-2-(2- methyl-2-(5-oxo-4,5-dihydro- 1,2,4-oxadiazol-3-yl)propyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 633 (M + H)+ 104H

(S)-1,1,1-trifluoro-2- methylpropan-2-yl (4-((3- chloro-1-ethyl-1H-pyrazol-4- yl)sulfonyl)-2-(2-methyl-2-(5- oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)propyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 637 (M + H)+ 104i

(S)-1,1,1-trifluoro-2- methylpropan-2-yl (4-((4- fluoro-3- methoxyphenyl)sulfonyl)-2-(2- methyl-2-(5-oxo-4,5-dihydro- 1,2,4-oxadiazol-3-yl)propyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 633 (M + H)+

Example 105 Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Example 105)

Step 1—Preparation of (S)-methyl 3-(4-benzyl-6-((tert-butoxycarbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate

To a mixture of (S)-dimethyl 2-((4-benzyl-6-((tert-butoxycarbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)malonate (10.00 g, 20.64 mmol) in DMSO (100 mL) was added LiCl (5.25 g, 124 mmol). The reaction was stirred at 140° C. for 8 hours, cooled to 25° C., diluted with water (200 mL) and extracted with ethyl acetate (3×300 mL). The organic layers were combined, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography (SiO₂, petroleum ether:EtOAc=20:1 to 5:1) to give the title compound as a light yellow solid. LCMS (ESI) calculated for C₂₄H₃₁N₂O₅ [M+H]⁺: 427. found: 427.2; ¹H NMR (CDCl₃, 400 MHz) δ 7.26-7.37 (5H, m), 6.73 (2H, d, J=8.6 Hz), 6.60 (1H, d, J=6.7 Hz), 6.22 (1H, br. s.), 4.44 (2H, s), 4.11 (1H, d, J=3.1 Hz), 3.68 (3H, s), 3.24 (1H, d, J=10.2 Hz), 3.10 (1H, dd, J=11.5, 7.6 Hz), 2.55 (2H, q, J=8.0 Hz), 1.89-1.98 (2H, m), 1.47 (9H, s).

Step 2—Preparation of (S)-tert-butyl (4-benzyl-2-(3-hydrazinyl-3-oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a mixture of (S)-methyl 3-(4-benzyl-6-((tert-butoxycarbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate (3.0 g, 7.03 mmol) in ethanol (40 mL) was added hydrazine hydrate (20 mL, 350 mmol) and Et₃N (2.94 mL, 21.10 mmol). The reaction mixture was stirred at 80° C. for 2 hours, cooled to 25° C. and concentrated in vacuo. The residual oil was diluted with H₂O (50 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, petroleum ether:EtOAc=3:1 to 1:10) to give the title compound as a yellow oil. LCMS (ESI) calculated for C₂₃H₃₁N₄O₄ [M+H]⁺: 427. found: 427.2; ¹H NMR (CDCl₃, 400 MHz) δ 7.23-7.39 (5H, m), 6.69-6.78 (2H, m), 6.64 (1H, br. s.), 6.37 (1H, br. s.), 4.44 (2H, s), 4.12-4.17 (1H, m), 3.21-3.27 (1H, m), 3.10 (1H, dd, J=11.7, 7.8 Hz), 2.35-2.46 (2H, m), 1.83-1.95 (2H, m), 1.48 (9H, s).

Step 3—Preparation of (S)-tert-butyl (4-benzyl-2-(2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a mixture of (S)-tert-butyl (4-benzyl-2-(3-hydrazinyl-3-oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (2.75 g, 6.45 mmol) in DMF (30 mL) was added Et₃N (2.70 mL, 19.34 mmol) and CDI (1.568 g, 9.67 mmol). The reaction was stirred at 25° C. for 3 hours, then diluted with water (100 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography (SiO₂, petroleum ether:EtOAc=10:1 to 3:1) to give the title compound as a yellow solid. LCMS (ESI) calculated for C₂₄H₂₉N₄O₅ [M+H]⁺: 453. found: 453.1; ¹H NMR (CDCl₃, 400 MHz) δ 7.24-7.37 (5H, m), 6.80 (1H, br. s.), 6.72 (1H, d, J=8.6 Hz), 6.59 (1H, d, J=7.0 Hz), 6.29 (1H, br. s.), 4.43 (2H, s), 4.15-4.20 (1H, m), 3.21-3.27 (1H, m), 3.09 (1H, dd, J=11.5, 7.6 Hz), 2.73-2.84 (2H, m), 1.89-2.02 (2H, m), 1.47 (9H, s).

Step 4—Preparation of (S)-5-(2-(6-amino-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1,3,4-oxadiazol-2(3H)-one

To a solution of (S)-tert-butyl (4-benzyl-2-(2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (2.86 g, 6.32 mmol) in DCM (30 mL) was added TFA (20 mL, 269 mmol), The reaction was stirred for 1 hour at 25° C., then concentrated in vacuo. The residual oil was diluted with DCM (50 mL), poured into aqueous NaHCO₃ and extracted with DCM (3×30 mL). The organic layers were combined, dried over Na₂SO₄, filtered and concentrated to afford the title compound as brown oil, which was used directly in the next step without further purification. LCMS (ESI) calculated for C₁₉H₂₁N₄O₃ [M+H]⁺: 353. found: 353.1; ¹H NMR (MeOD, 400 MHz) δ 7.17-7.34 (6H, m), 6.58 (1H, s), 6.29 (1H, s), 4.44 (2H, q, J=16.4 Hz), 3.14 (1H, dd, J=11.5, 7.6 Hz), 2.67-2.85 (2H, m), 1.93-1.99 (2H, m).

Step 5—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-benzyl-2-(2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a mixture of (S)-5-(2-(6-amino-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1,3,4-oxadiazol-2(3H)-one (2.05 g, 5.82 mmol) in DMSO (20 mL) was added 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (1.551 g, 6.98 mmol) and concentrated HCl (0.25 mL, 3.04 mmol). The reaction was stirred at 80° C. for 5 hours, then diluted with water (50 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography (SiO₂, petroleum ether:EtOAc=10:1 to 2:1) to give the title compound as yellow oil. LCMS (ESI) calculated for C₂₄H₂₆F₃N₄O₅ [M+H]⁺: 507. found: 507.2; ¹H NMR (CDCl₃, 400 MHz) δ 7.26-7.37 (5H, m), 6.71-6.80 (2H, m), 6.63 (1H, br. s.), 6.49 (1H, br. s.), 4.44 (2H, s), 4.16-4.20 (1H, m), 3.26 (1H, dd, J=11.7, 2.3 Hz), 3.12 (1H, dd, J=11.7, 7.4 Hz), 2.74-2.86 (2H, m), 1.91-2.02 (2H, m), 1.72 (6H, s).

Step 6—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a mixture of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-benzyl-2-(2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl) carbamate (2.72 g, 5.37 mmol) in THF (100 mL) was added Pd/C (10%, 0.50 g, 0.470 mmol) under argon. The suspension was degassed under vacuum and purged with H₂ several times. The reaction was stirred under H₂ balloon (1 atm) at 25° C. for 12 hours, then filtered through a pad of CELITE and the filtrate concentrated to dryness to afford the title compound as a yellow solid, which was used directly in the next step without further purification. LCMS (ESI) calculated for C₁₇H₂₀F₃N₄O₅ [M+H]⁺: 417. found: 417.2; ¹H NMR (MeOD, 400 MHz) δ 6.77 (1H, br. s.), 6.47-6.58 (2H, m), 4.03 (1H, q, J=5.9 Hz), 3.32 (1H, d, J=2.0 Hz), 3.03 (1H, dd, J=11.9, 7.6 Hz), 2.71-2.82 (2H, m), 1.96 (2H, q, J=7.4 Hz), 1.70 (6H, s).

Step 7—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a mixture of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (30 mg, 0.072 mmol) in THF (1.0 mL) was added 3-chloro-1-ethyl-1H-pyrazole-4-sulfonyl chloride (33.0 mg, 0.144 mmol) and pyridine (1.0 mL). The reaction was stirred at 25° C. for 12 hours, then diluted with EtOAc (5 mL) and water (10 mL). The aqueous layer was extracted with EtOAc (3×5 mL). The combined organic phase was dried over Na₂SO₄ and concentrated in vacuo. The crude product was purified by prep-HPLC (MeCN/water using TFA buffer) to afford the title compound as a white solid. LCMS (ESI) calculated for C₂₂H₂₅ClF₃N₆O₇S [M+H]⁺: 609. found: 609.1; ¹H NMR (MeOD, 400 MHz) δ 9.39 (1H, br. s.), 8.34 (1H, t, J=7.6 Hz), 8.11 (1H, br. s.), 6.77-6.87 (2H, m), 6.73 (1H, s), 4.40 (1H, dd, J=13.7, 1.6 Hz), 4.00-4.13 (3H, m), 3.40 (1H, dd, J=13.7, 9.0 Hz), 2.78-2.87 (2H, m), 2.01-2.14 (2H, m), 1.75 (6H, s), 1.47 (3H, t, J=7.2 Hz).

Example 106 Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Example 106)

Step 1—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyano-2-methylpropyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

(R and S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyano-2-methylpropyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (see Example 94; 46 g, 84.5 mmol) was resolved by SFC (Column: Chiralpak AD (250×30 mm I.D., 10 um); Mobile phase: Supercritical CO₂/MeOH (0.1%) NH₃.H₂O=70/30 at 80 mL/min; Column Temp: 38° C.; Nozzle Pressure: 100Ba; Wavelength: 220 nm) to give the titled compound (faster eluent, Isomer 1) as yellow solid. LCMS (ESI) calculated for C₂₅H₂₉F₃N₃O₅S [M+H]⁺: 540.2. found: 540.2.

Step 2—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2,2-dimethyl-3-oxopropyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-cyano-2-methylpropyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (10 g, 18.53 mmol) in toluene (600 mL) was added DIBAL-H (74.1 ml, 74.1 mmol) dropwise at −78° C. under nitrogen. The reaction was stirred at −78° C. for 1 h, then quenched with MeOH (74 mL) and acidified with 1M HCl (244 mL). After stirring at 0° C. for 10 min, the resulting solution was extracted with EtOAc (500 mL×3) and the combined organic layers washed with brine, dried over Na₂SO₄ and evaporated to dryness. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=3:1) to give the title compound as yellow solid. LCMS (ESI) calculated for C₂₅H₃₀F₃N₂O₆S [M+H]⁺: 543.2. found: 543.1.

Step 3—Preparation of (S)-2,2-dimethyl-3-(4-tosyl-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoic acid

To a solution of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2,2-dimethyl-3-oxopropyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (10.5 g, 19.35 mmol) in THF (400 mL) and water (80 mL) were added sulfamic acid (11.27 g, 116 mmol), potassium dihydrogenphosphate (31.6 g, 232 mmol) and sodium chlorite (2.63 g, 29.0 mmol) at 0° C. The reaction was stirred at 0° C. for 1 h, then diluted with water (250 mL) and extracted with EtOAc (3×500 mL). The combined organic layers were dried over Na₂SO₄ and evaporated to dryness. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1 to 1:1) to afford the title compound as yellow solid. LCMS (ESI) calculated for C₂₅H₃₀F₃N₂O₇S [M+H]⁺: 559.2. found: 559.2.

Step 4—Preparation of (S)-tert-butyl 2-(2,2-dimethyl-3-(4-tosyl-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoyl)hydrazinecarboxylate

To a solution of (S)-2,2-dimethyl-3-(4-tosyl-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoic acid (650 mg, 1.164 mmol) and Et₃N (0.250 mL, 1.790 mmol) in CH₂Cl₂ (15 mL) was added HATU (442 mg, 1.164 mmol). The mixture was stirred at 25° C. for 1 h, then treated with tert-butyl hydrazinecarboxylate (237 mg, 1.790 mmol). The mixture was stirred at 25° C. for 16 h, concentrated and the solid residue was purified by column chromatography (petroleum ether:EtOAc=2:1) to give the title compound as colorless oil. LCMS (ESI) calculated for C₃₀H₄₀F₃N₄O₈S [M+H]⁺: 673.2. found: 673.2.

Step 5—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(3-hydrazinyl-2,2-dimethyl-3-oxopropyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-tert-butyl 2-(2,2-dimethyl-3-(4-tosyl-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoyl)hydrazinecarboxylate (430 mg, 0.639 mmol) in ethyl acetate (3 ml) was added a solution of HCl in EtOAc (10 ml, 4 M). The reaction was stirred at 20° C. for 2 h, then concentrated to give the crude title compound as light yellow solid. LCMS (ESI) calculated for C₂₅H₃₂F₃N₄O₆S [M+H]⁺: 573.2. found: 573.1.

Step 6-Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-methyl-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(3-hydrazinyl-2,2-dimethyl-3-oxopropyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (376 mg, 0.657 mmol) and N-ethyl-N-isopropylpropan-2-amine (255 mg, 1.970 mmol) in DMF (5 mL) was added di(1H-imidazol-1-yl)methanone (160 mg, 0.985 mmol). The reaction was stirred at 25° C. for 6 h, then concentrated in vacuo. The crude product was purified by prep-TLC (petroleum ether:EtOAc=1:1) to give the title compound as yellow oil. LCMS (ESI) calculated for C₂₆H₃₀F₃N₄O₇S [M+H]⁺: 599.2. found: 599.2.

Step 7—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-methyl-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-methyl-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (340 mg, 0.568 mmol) in MeOH (20 mL) was added Mg (276 mg, 11.36 mmol) in one portion at 25° C. under nitrogen. The reaction was stirred at 25° C. for 18 hours, then quenched with saturated NH₄Cl solution and extracted with EtOAc (3×300 mL). The combined organic layers were dried over Na₂SO₄, filtered and the filtrate concentrated in vacuo. The crude product was purified by prep-TLC (petroleum ether:EtOAc=1:1) to afford the title compound as yellow solid. LCMS (ESI) calculated for C₁₉H₂₄F₃N₄O₅ [M+H]⁺: 445.2. found: 445.2; ¹H-NMR (400 MHz, MeOD) δ 6.85 (1H, s), 6.54 (1H, d, J=7.6 Hz), 6.39 (1H, d, J=8.8 Hz), 4.07-4.12 (1H, m), 3.24-3.25 (1H, m), 3.01-3.09 (2H, m), 1.99-2.08 (2H, m), 1.70 (6H, s), 1.25-1.41 (6H, m), 0.93-0.95 (1H, m).

Step 8—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a mixture of (S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-methyl-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (30 mg, 0.068 mmol) in THF (0.5 mL) was added 3-chloro-1-ethyl-1H-pyrazole-4-sulfonyl chloride (30.9 mg, 0.135 mmol) and pyridine (0.5 mL). The reaction mixture was stirred at 20° C. for 6 hours, then diluted with water (3 mL) and extracted with ethyl acetate (3×5 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by prep-HPLC (MeCN/water using TFA buffer) to afford the title compound as white solid. LCMS (ESI) calculated for C₂₄H₂₉ClF₃N₆O₇S [M+H]⁺: 637.1. found: 637.1; ¹H-NMR (400 MHz, MeOD) δ 8.24 (1H, s), 7.87 (1H, s), 6.90-6.93 (1H, m), 6.52 (1H, d, J=9.2 Hz), 4.23 (1H, d, J=12.4 Hz), 4.10 (2H, q, J=7.2 Hz), 3.87-3.92 (1H, m), 3.33-3.36 (1H, m), 1.96-2.02 (1H, m), 1.81-1.84 (1H, m), 1.74 (6H, s), 1.32-1.41 (9H, m).

Example 107 Preparation of additional 1,3,4-oxadiazolone

The compounds in Table 31 below were prepared based on the experimental procedures described in Examples 105 and 106 and elsewhere in the detailed description, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 31 Ex. Observed No. Structure Name m/z 107A

2,2,2-trifluoro-1,1- dimethylethyl {(2S)-4-[(3- cyclopropylphenyl)sulfonyl]- 2-[2-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)ethyl]- 3,4-dihydro-2H-1,4- benzoxazin-6-yl}carbamate 597 (M + H)+ 107B

2,2,2-trifluoro-1,1- dimethylethyl {(2S)-4-[(4- fluoro-3- methoxyphenyl)sulfonyl]- 2-[2-methyl-2-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2- yl)propyl]-3,4-dihydro-2H- 1,4-benzoxazin-6- yl}carbamate 633 (M + H)+

Example 108 Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(1H-tetrazol-5-yl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Example 108)

To a solution of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyanoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (50 mg, 0.08 mmol) and sodium azide (28.7 mg, 0.4 mmol) in DMF (1 mL) was added NH₄Cl (23.6 mg, 0.4 mmol). The reaction was stirred at 110° C. for 6 h under N₂, then cooled and treated with water (10 mL). The biphasic mixture was extracted with ethyl acetate (10 mL) and the combined organic layers were washed with aqueous sodium hydroxide (10 mL), dried (Na₂SO₄), filtered and evaporated under reduced pressure. The crude product was purified by prep-HPLC (MeCN/water using TFA buffer) to afford the title compound as white solid. LCMS (ESI) calculated for C₂₃H₂₃F₆N₆O₅S [M+H]⁺: 609. found: 609. ¹H NMR (CDCl₃, 400 MHz) δ 7.95 (brs, 1H), 7.74-7.90 (m, 3H), 7.54-7.63 (m, 1H), 6.91-7.00 (m, 1H), 6.52-6.72 (m, 2H), 4.16 (d, J=12.9 Hz, 1H), 3.58 (brs, 1H), 3.23-3.35 (m, 1H), 3.07 (t, J=6.8 Hz, 2H), 1.97-2.09 (m, 2H), 1.70 (brs, 7H).

Example 109 Preparation of Additional Tetrazoles

The compounds in Table 32 below were prepared based on the experimental procedures described in Example 108 and elsewhere in the detailed description, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 32 Ex. Observed No. Structure Name m/z 109A

2,2,2-trifluoro-1,1-dimethylethyl {(2S)-4-[(3- cyclopropylphenyl)sulfonyl]-2-[2- (1H-tetrazol-5-yl)ethyl]-3,4- dihydro-2H-1,4-benzoxazin-6- yl}carbamate 581 (M + H)+ 109B

2,2,2-trifluoro-1,1-dimethylethyl [(2S)-2-[2-(1H-tetrazol-5-yl)ethyl]- 4-{[2-(trifluoromethyl)pyridin-4- yl]sulfonyl}-3,4-dihydro-2H-1,4- benzoxazin-6-yl]carbamate 610 (M + H)+ 109C

(S)-1,1,1-trifluoro-2-methylpropan- 2-yl (2-(2-(1H-tetrazol-5-yl)ethyl)- 4-((3-chloro-1-ethyl-1H-pyrazol-4- yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 593 (M + H)+

Example 110 Preparation of (R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(hydroxymethyl)-5-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Example 110)

Step 1—Preparation of (R)-(5-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methanol

-   (S)-2-(chloromethyl)oxirane (902 mg, 9.74 mmol) was added dropwise     to a stirred mixture of 2-amino-3-methylphenol (1.00 g, 8.12 mmol)     and AcOH (1.40 mL, 24.4 mmol) in ethanol (50 mL) at 100° C. under     nitrogen and the resulting mixture was stirred at 100° C. for 1 h.     K₂CO₃ (6.73 g, 48.7 mmol) was next added and the resulting solution     was stirred at 100° C. for an additional 16 h. The reaction was     evaporated under reduced pressure and the residue dissolved in     EtOAc, washed with water and brine (50 mL), dried over Na₂SO₄,     filtered and concentrated. The crude product was purified by silica     gel column chromatography (EtOAc in petroleum ether from 0 to 33%)     to afford the title compound as brown oil.

Step 2—Preparation of (R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine

A solution of (R)-(5-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methanol (450 mg, 2.51 mmol), 1H-imidazole (400 mg, 5.88 mmol) and tert-butylchlorodimethylsilane (700 mg, 4.64 mmol) in DMF (2 mL) was stirred at 40-50° C. for 6 h. The reaction was then cooled and diluted with EtOAc, washed with brine, dried Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography on silica gel (EtOAc:petroleum ether=1:20-1:5) to afford the title compound as a yellow oil. LCMS (ESI) calculated for C₁₆H₂₈NO₂Si [M+H]⁺: 294.2. found: 294.1, ¹H NMR (400 MHz, DMSO) δ 6.53 (dd, J=15.6 Hz, 7.4 Hz, 2H), 6.34-6.45 (m, 1H), 5.16 (s, 1H), 3.95 (d, J=5.3 Hz, 1H), 3.65-3.85 (m, 2H), 3.38 (d, J=2.7 Hz, 1H), 3.32 (s, 1H), 3.00-3.15 (m, 1H), 2.03 (s, 3H), 0.88 (s, 9H), 0.07 (d, J=4.7 Hz, 6H).

Step 3—Preparation of (R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

A solution of (R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (100 mg, 0.341 mmol) and 3-(trifluoromethyl)benzene-1-sulfonyl chloride (100 mg, 0.409 mmol) in DCM (1 mL) and pyridine (1 mL) was stirred at room temperature for 16 h. The reaction was then acidified with 0.5 M HCl to pH=5-6 and extracted with EtOAc. The combined organic layers were washed with brine, dried with Na₂SO₄ and concentrated. The crude product was purified by column chromatography on silica gel to afford the title compound as a yellow oil. LCMS (ESI) calculated for C₂₃H₃₁F₃NO₄SSi [M+H]⁺: 502.2. found: 502.2, ¹H NMR (400 MHz, CDCl₃) δ 7.77-7.90 (m, 3H), 7.55-7.66 (m, 1H), 7.05-7.13 (m, 1H), 6.89 (d, J=7.4 Hz, 1H), 6.61 (d, J=8.0 Hz, 1H), 4.24 (d, J=12.3 Hz, 1H), 3.88 (dd, J=10.4 Hz, 4.7 Hz, 1H), 3.49-3.65 (m, 2H), 3.30 (s, 1H), 2.51 (s, 3H), 0.81 (s, 10H), 0.00 (s, 3H), −0.03 (s, 3H).

Step 4—Preparation of (R)-(5-methyl-6-nitro-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methanol

To a solution of (R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (300 mg, 0.598 mmol) in MeNO₂ (2 mL) was added nitroniumte trafluoroborate (100 mg, 0.753 mmol) in one batch, then the reaction mixture was stirred at 0° C. for 3 h. The reaction mixture was directly purified by preparative TLC to afford the title compound as a white solid. LCMS (ESI) calculated for C₁₇H₁₆F₃N₂O₆S [M+H]⁺: 433.1. found: 433.2, ¹H NMR (400 MHz, CDCl₃) δ 7.88-8.00 (m, 4H), 7.62-7.73 (m, 1H), 6.82 (d, J=9.2 Hz, 1H), 4.19-4.29 (m, 1H), 3.60-3.84 (m, 3H), 3.28-3.41 (m, 1H), 2.60-2.67 (m, 3H).

Step 5—Preparation of (R)-(6-amino-5-methyl-4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methanol

HCl (2.0 Min MeOH, 1.0 mL) was added to a solution of (R)-(5-methyl-6-nitro-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methanol (120 mg, 0.278 mmol) and iron powder (150 mg, 2.69 mmol) in methanol (2 mL) and the resulting solution was stirred at room temperature for 1 h. The reaction was next filtered through CELITE and washed with methanol. The filtrate was concentrated to afford the title compound. LCMS (ESI) calculated for C₁₇H₁₈F₃N₂O₄S [M+H]⁺: 403.1. found: 403.0.

Step 6—Preparation of (R)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(hydroxymethyl)-5-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R)-(6-amino-5-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methanol (100 mg, 0.249 mmol) in DMSO (1 mL) was added (1-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-1H-imidazol-3-ium-3-yl)methanide iodide (117 mg, 0.323 mmol) and the resultant mixture was stirred at room temperature for 1 h. Water was then added and the biphasic mixture extracted with EtOAc (10 mL×2). The combined organic layers were washed with water and brine, concentrated and the crude product purified by preparative HPLC (MeCN/water using TFA buffer) to afford the title compound as a white solid. LCMS (ESI) calculated for C₂₂H₂₃F₆N₂O₆S [M+H]⁺: 557.1. found: 557.2, ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.97 (m, 4H), 6.68 (d, J=8.4 Hz, 1H), 6.50 (s, 1H), 4.24 (d, J=12.5 Hz, 1H), 3.87 (s, 1H), 3.65 (d, J=11.9 Hz, 1H), 3.19-3.39 (m, 1H), 2.38 (s, 3H), 1.77 (d, J=6.3 Hz, 6H).

Example 111 Preparation of (R)-1,1,1-trifluoro-2-methylpropan-2-yl (5-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate and (S)-1,1,1-trifluoro-2-methylpropan-2-yl (5-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate (Examples 111A and 111B)

Step 1—Preparation of 1-benzyl-7-chloro-3,4-dihydro-1,5-naphthyridin-2(1H)-one

To a 0° C. solution of 7-chloro-3,4-dihydro-1,5-naphthyridin-2(1H)-one (2 g, 10.95 mmol) in N,N-dimethylformamide (20 mL) was added Cs₂CO₃ (5.35 g, 16.43 mmol), followed by (bromomethyl)benzene (2.061 g, 12.05 mmol). The reaction mixture was stirred at room temperature for 1 hour, then poured into water (50 mL) and extracted with EtOAc (50 ml×3). The combined organic layers were washed with brine (50 ml×3), dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude product was purified by column chromatography on silica gel (EtOAc:petroleum ether=0-30%) to afford the titled compound as a yellow solid. LCMS (ESI) calculated for C₁₅H₁₄ClN₂O [M+H]⁺: 273. found: 273. ¹HNMR (400 MHz, CDCl₃) δ 8.12 (1H, s), 7.26-7.36 (3H, m), 7.19 (2H, d, J=7.2 Hz), 7.11 (1H, s), 5.11 (2H, s), 3.18 (2H, t, J=7.6 Hz), 2.90 (2H, t, J=8.0 Hz).

Step 2—Preparation of (R and S)-1-benzyl-7-chloro-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carboxylate

To a −78° C. solution of 1-benzyl-7-chloro-3,4-dihydro-1,5-naphthyridin-2(1H)-one (2 g, 7.33 mmol) in dry tetrahydrofuran (50 mL) was added LHMDS (8.80 mL, 8.80 mmol, 1M in THF) and the mixture was stirred at −78° C. for 30 minutes. Methyl carbonochloridate (0.832 g, 8.80 mmol) was next added and the reaction was stirred at −78° C. for an additional 1 hour. The reaction was quenched with saturated aq. NH₄Cl (20 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL×3), dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude product was purified by column chromatography on silica gel (EtOAc:petroleum ether=0-30%) to afford the titled compound as a yellow solid. LCMS (ESI) calculated for C₁₇H₁₆ClN₂O₃ [M+H]⁺: 331. found: 331. ¹HNMR (400 MHz, CDCl₃) δ 8.15 (1H, s), 7.25-7.35 (5H, m), 7.13 (1H, s), 5.31 (1H, d, J=16.4 Hz), 5.31 (1H, d, J=16.4 Hz), 3.91 (1H, t, J=6.8 Hz), 3.78 (3H, s), 3.58 (1H, dd, J=7.2 Hz J=16.4 Hz), 3.40 (1H, dd, J=6.4 Hz J=17.2 Hz).

Step 3—Preparation of (R and S)-1-benzyl-7-chloro-3-(methoxymethyl)-1,2,3,4-tetrahydro-1,5-naphthyridine

To a 0° C. solution of methyl 1-benzyl-7-chloro-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carboxylate (1.7 g, 5.14 mmol) in dry tetrahydrofuran (50 mL) was added BH₃—SMe₂ (2.440 mL, 25.7 mmol). The reaction mixture was stirred at 60° C. for 2 hours, then quenched with MeOH (10 mL) and concentrated under vacuum. The crude product was purified by column chromatography on silica gel (EtOAc:petroleum ether=0-30%) to afford the titled compound as a yellow solid. LCMS (ESI) calculated for C₁₆H₁₈ClN₂O [M+H]⁺: 289. found: 289. ¹HNMR (400 MHz, CDCl₃) δ 7.80 (1H, d, J=1.6 Hz), 7.10-7.31 (5H, m), 6.82 (1H, d, J=2.0 Hz), 4.45 (2H, q, J=16.8, 27.2 Hz), 3.77 (1H, d, J=10.8 Hz), 3.48-3.52 (3H, m), 3.28 (1H, t, J=9.2 Hz), 2.79 (1H, q, J=10.0, 18.4 Hz), 2.27-2.29 (1H, m), 1.56-1.54 (1H, m).

Step 4—Preparation of (R and S)-(1-benzyl-7-chloro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl methanesulfonate

To a solution of (R and S)-(1-benzyl-7-chloro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methanol (2000 mg, 6.93 mmol) and Et₃N (1.931 mL, 13.85 mmol) in dry DCM (20 mL) at 0° C. was added methanesulfonyl chloride (2500 mg, 21.82 mmol). The reaction mixture was stirred at 20° C. for 10 hours, then quenched with water (20 mL). The biphasic mixture was extracted with DCM (3×20 mL) and the combined organic layer was dried over Na₂SO₄ and evaporated. The crude product was purified by column chromatography (SiO₂, petroleum ether:EtOAc=20:1 to 2:1) to give the title compound as a colorless oil. ¹HNMR (CDCl3, 400 MHz) δ 7.80 (1H, s), 7.34-7.38 (2H, m), 7.30 (1H, d, J=7.2 Hz), 7.19-7.21 (2H, m), 6.81 (1H, s), 4.48 (2H, s), 4.28 (1H, dd, J=10.0, 5.2 Hz), 4.16-4.21 (1H, m), 3.50-3.50 (1H, m), 3.31-3.34 (1H, m), 3.11-3.12 (1H, m), 3.00 (3H, s), 2.81-2.83 (1H, m), 2.62-2.64 (1H, m).

Step 5—Preparation of (R and S)-1-benzyl-7-chloro-3-(iodomethyl)-1,2,3,4-tetrahydro-1,5-naphthyridine

To a solution of (R and S)-(1-benzyl-7-chloro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl methanesulfonate (350 mg, 0.954 mmol) in acetone (10 mL) was added NaI (143 mg, 0.954 mmol). The reaction mixture was stirred at 60° C. for 10 hours, then concentrated under vacuum, diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layer was dried over Na₂SO₄, evaporated and the crude product was purified by column chromatography (petroleum ether:EtOAc=20:1 to 5:1) to give the title compound as a colorless oil. ¹H-NMR (CDCl₃, 400 MHz) δ 7.79 (1H, d, J=0.4 Hz), 7.35-7.39 (2H, m), 7.31 (1H, d, J=7.2 Hz), 7.21-7.23 (2H, m), 6.77 (1H, s), 4.49 (2H, s), 3.52 (1H, d, J=1.2 Hz), 3.28-3.30 (2H, m), 3.17-3.22 (2H, m), 3.80-3.83 (1H, m), 2.34-2.37 (1H, m).

Step 6—Preparation of (R and S)-1-benzyl-7-chloro-3-((ethylsulfonyl)methyl)-1,2,3,4-tetrahydro-1,5-naphthyridine

To a solution of (R and S)-1-benzyl-7-chloro-3-(iodomethyl)-1,2,3,4-tetrahydro-1,5-naphthyridine (550 mg, 1.380 mmol) in DMF (10 ml) at 0° C. was added sodium ethanesulfinate (481 mg, 4.14 mmol). The reaction mixture was stirred at 110° C. for 1 h in the microwave, then cooled to room temperature, quenched with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layer was washed with brine (30 mL×3), dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by column chromatography (SiO₂, petroleum ether:EtOAc=1:3) to give the title compound as a brown solid. LCMS (ESI) calculated for C₁₈H₂₂ClN₂O₂S [M+H]+: 365.1. found: 365.0. ¹H-NMR (CDCl3, 400 MHz) δ 7.78 (1H, s), 7.32-7.36 (2H, m), 7.27-7.29 (1H, m), 7.19-7.21 (2H, m), 6.81 (1H, d, J=1.2 Hz), 4.49 (2H, s), 3.67-3.70 (1H, m), 3.45-3.48 (1H, m), 3.20-3.24 (1H, m), 2.97-3.03 (4H, m), 2.80-2.84 (1H, m), 1.39 (3H, t, J=7.6 Hz).

Step 7—Preparation of (R and S)-5-benzyl-N-(diphenylmethylene)-7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-amine

A mixture of (R and S)-1-benzyl-7-chloro-3-((ethylsulfonyl)methyl)-1,2,3,4-tetrahydro-1,5-naphthyridine (350 mg, 0.959 mmol) in dioxane (10 ml) was added diphenylmethanimine (209 mg, 1.151 mmol), Cs₂CO₃ (625 mg, 1.918 mmol) and chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl) palladium(ii) methyl-t-butyl ether adduct (159 mg, 0.192 mmol). The reaction mixture degassed under argon and stirred at 110° C. for 10 hours, then diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layer was washed with brine (10 mL×3), dried over Na₂SO₄ and concentrated under pressure. The crude product was purified by Prep-TLC (SiO₂, petroleum ether:EtOAc=1:2) to give the title compound as a yellow solid. LCMS (ESI) calculated for C₃₁H₃₂N₃O₂S [M+H]+: 510.2. found: 510.2. ¹H-NMR (CDCl3, 400 MHz) δ 7.74 (1H, d, J=7.6 Hz), 7.60 (1H, d, J=7.6 Hz), 7.41-7.42 (3H, m), 7.30-7.32 (2H, m), 7.23-7.24 (3H, m), 7.17-7.18 (2H, m), 6.99-7.01 (2H, m), 6.92-6.94 (2H, m), 6.20 (1H, s), 4.26 (2H, d, J=3.6 Hz), 3.54 (1H, d, J=10.4 Hz), 3.29-3.32 (1H, m), 3.05-3.09 (1H, m), 2.89-2.94 (4H, m), 2.81-2.83 (1H, m), 2.66-2.71 (1H, m), 1.30 (3H, t, J=7.6 Hz).

Step 8—Preparation of (R and S)-7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-amine

Pd/C (146 mg, 0.137 mmol) was added to a solution of the (R and S)-5-benzyl-N-(diphenylmethylene)-7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-amine (140 mg, 0.275 mmol) in MeOH (20 mL). The resulting mixture was stirred under H₂ atmosphere (50 psi) at 40° C. for 16 hours, then filtered. The filtrate was concentrated under vacuum to afford crude title compound as a yellow oil. LCMS (ESI) calculated for C₁₁H₁₈N₃O₂S [M+H]⁺: 256.1. found: 256.2.

Step 9—Preparation of (R)-1,1,1-trifluoro-2-methylpropan-2-yl (7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate and (S)-1,1,1-trifluoro-2-methylpropan-2-yl (7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

To a mixture of (R and S)-7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-amine (60 mg, 0.00 mmol) and 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (78 mg, 0.352 mmol) in DMSO (5 mL) was added concentrated hydrogen chloride (0.016 mL, 0.188 mmol) and the resulting reaction stirred at 80° C. for 3 hours. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×15 mL). The organic layer was washed with brine (3×10 mL), dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by Prep-TLC to give the titled racemate as a yellow solid.

The above racemate was separated by SFC (Instrument: Thar SFC 350; Column: AD (250 mm*30 mm, 10 um), 10 um; Mobile phase: 40% MEOH NH₃H₂O, 80 ML/MIN; Column Temp: 38° C.; Nozzle Pressure: 100 Bar Nozzle Temp: 60° C.) to give both enantiomers (faster eluent, Peak 1 from Step 9; slower eluent, Peak 2 from Step 9), which have the same analytical data: LCMS (ESI) calculated for C₁₆H₂₃F₃N₃O₄S [M+H]⁺: 410.1. found: 410.1.

Step 10—Preparation of (R)-1,1,1-trifluoro-2-methylpropan-2-yl (5-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate and (S)-1,1,1-trifluoro-2-methylpropan-2-yl (5-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

To a mixture of (R or S)-1,1,1-trifluoro-2-methylpropan-2-yl(7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate (Peak 1 from Step 9, 12 mg, 0.029 mmol) in tetrahydrofuran (1.5 mL) and pyridine (1.5 mL) was added 3-chloro-1-ethyl-1H-pyrazole-4-sulfonyl chloride (20.14 mg, 0.088 mmol) and DMAP (3.58 mg, 0.029 mmol). The reaction mixture was stirred at 100° C. for 1.5 hours in a microwave, then cooled to room temperature and directly purified by Prep-HPLC to afford the titled compound (Isomer 1, Example 111A) as brown solid.

The other enantiomer (Isomer 2, Example 111B) was prepared using a similar procedure from Peak 2 from Step 9. Both enantiomers have same analytical data: LCMS (ESI) calculated for C₂₁H₂₈ClF₃N₅O₆S₂ [M+H]+: 602.1. found: 607.1; ¹H-NMR (Methanol-d4, 400 MHz) δ 8.83 (1H, s), 8.45 (1H, s), 8.33 (1H, s), 8.01-8.02 (1H, m), 4.16 (2H, q, J=7.2 Hz), 3.40-3.46 (2H, m), 3.10-3.19 (4H, m), 2.74-2.81 (2H, m), 2.53-2.55 (1H, m), 1.78 (6H, s), 1.46 (3H, t, J=6.8 Hz), 1.36 (3H, t, J=7.6 Hz).

Example 112 Preparation of (S)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoic acid and (R)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoic acid (Example 112A and 112B)

Step 1—Preparation of (E)-ethyl 3-(3-amino-5-chloropyridin-2-yl)acrylate

To a solution of 2,5-dichloropyridin-3-amine (5 g, 30.7 mmol) in DMF (50 ml) were added ethyl acrylate (3.69 g, 36.8 mmol), DIPEA (8.04 ml, 46.0 mmol), Pd(OAc)₂ (0.689 g, 3.07 mmol), Bu₄NBr (0.989 g, 3.07 mmol) and (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.910 g, 3.07 mmol). The reaction mixture was heated to 140° C. and stirred for 30 hours. The reaction mixture was cooled to room temperature, and then poured into water (200 mL), extracted with EtOAc (200 mL×3), the combined organic layers were washed by brine (200 mL×3), dried over anhydrous Na₂SO₄ and evaporated under vacuum. The crude product was purified by silica gel column chromatography (EtOAc:petroleum ether=0-30%) to afford (E)-ethyl 3-(3-amino-5-chloropyridin-2-yl)acrylate as a yellow solid. LCMS (ESI) calculated for C₁₀H₁₂ClN₂O₂[M+H]⁺: 227.1. found: 227.2.

Step 2—Preparation of ethyl 3-(3-amino-5-chloropyridin-2-yl)propanoate

Pd/C (2.35 g, 2.21 mmol) was added to a solution of the (E)-ethyl 3-(3-amino-5-chloropyridin-2-yl)acrylate (2.5 g, 11.03 mmol) in MeOH (10 ml). The mixture was stirred under H₂ atmosphere (1 atm) at 0° C. for 2 h and then filtered. The filtrate was concentrated under vacuum and the crude product was purified by column chromatography on silica gel (EtOAc:petroleum ether=0-30%) to afford ethyl 3-(3-amino-5-chloropyridin-2-yl)propanoate as a yellow solid. LCMS (ESI) calculated for C₁₀H₁₄ClN₂O₂ [M+H]⁺: 229.1. found: 229.1.

Step 3—Preparation of 7-chloro-3,4-dihydro-1,5-naphthyridin-2(1H)-one

AcOH (1.502 ml, 26.2 mmol) was added to a solution of the ethyl 3-(3-amino-5-chloropyridin-2-yl)propanoate (2 g, 8.75 mmol) in tetrahydrofuran (50 ml). The mixture was heated to 60° C. and stirred for 2 hours. The reaction mixture was concentrated under vacuum and the crude product was purified by column chromatography on silica gel (EtOAc:petroleum ether=0-30%) to afford 7-chloro-3,4-dihydro-1,5-naphthyridin-2(1H)-one as a yellow solid. LCMS (ESI) calculated for C₈H₈ClN₂O [M+H]⁺: 183.0. found: 183.1.

Step 4—Preparation of 1-benzyl-7-chloro-3,4-dihydro-1,5-naphthyridin-2(1H)-one

At 0° C., to a solution of 7-chloro-3,4-dihydro-1,5-naphthyridin-2(1H)-one (2 g, 10.95 mmol) in N,N-dimethylformamide (20 mL) was added Cs₂CO₃ (5.35 g, 16.43 mmol), followed by (bromomethyl)benzene (2.061 g, 12.05 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (50 mL), then extracted with EtOAc (50 ml×3). The combined organic layers were washed with brine (50 ml×3), dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude product was purified by column chromatography on silica gel (EtOAc:petroleum ether=0-30%) to afford 1-benzyl-7-chloro-3,4-dihydro-1,5-naphthyridin-2(1H)-one as a yellow solid. LCMS (ESI) calculated for C₁₅H₁₄ClN₂O [M+H]⁺: 273.1. found: 273.2.

Step 5—Preparation of (R and S)-methyl 1-benzyl-7-chloro-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carboxylate

At −78° C., to a solution of 1-benzyl-7-chloro-3,4-dihydro-1,5-naphthyridin-2(1H)-one (2 g, 7.33 mmol) in dry tetrahydrofuran (50 mL) was added LHMDS (8.80 mL, 8.80 mmol), the mixture was stirred at −78° C. for 30 minutes, then methyl carbonochloridate (0.832 g, 8.80 mmol) was added. The reaction mixture was stirred at −78° C. for 1 hour and quenched with saturated solution of NH₄Cl (20 mL). The aqueous layer was extracted with EtOAc (50 mL×3) and the combined organic layers were washed with brine (50 mL×3), dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel (EtOAc:petroleum ether=0-30%) to afford (R and S)-methyl 1-benzyl-7-chloro-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carboxylate as a yellow solid. LCMS (ESI) calculated for C₁₇H₁₆ClN₂O₃[M+H]⁺: 331.1. found: 331.2.

Step 6—Preparation of (R and S)-(1-benzyl-7-chloro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methanol

At 0° C., to a solution of (R and S)-methyl 1-benzyl-7-chloro-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carboxylate (1.7 g, 5.14 mmol) in dry tetrahydrofuran (50 ml) was added BH₃—SMe₂ (2.440 mL, 25.7 mmol) and the reaction mixture was stirred at 60° C. for 2 hours. The reaction was quenched with MeOH (10 mL), then concentrated under vacuum. The crude product was purified by column chromatography on silica gel (EtOAc:petroleum ether=0-30%) to afford the title compound as a yellow solid. LCMS (ESI) calculated for C₁₆H₁₈ClN₂O [M+H]⁺: 289.1. found: 289.2.

Step 7—Preparation of (S and R)-1-benzyl-3-(bromomethyl)-7-chloro-1,2,3,4-tetrahydro-1,5-naphthyridine

To a solution of (R and S)-(1-benzyl-7-chloro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methanol (500 mg, 1.731 mmol) and CBr₄ (1263 mg, 3.81 mmol) in THF (20 ml) was added Ph₃P (1045 mg, 3.98 mmol) portionwise. The reaction mixture was stirred at 60° C. for 16 hours, then concentrated in vacuo. The crude product was purified by column chromatography on silica gel (EtOAc:petroleum ether=0-20%) to give the title compound as a yellow solid. LCMS (ESI) calculated for C₁₆H₁₇BrClN₂ [M+H]⁺: 351.0. found: 351.1.

Step 8—Preparation of (R and S)-diethyl 2-((1-benzyl-7-chloro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)malonate

To a solution of (S and R)-1-benzyl-3-(bromomethyl)-7-chloro-1,2,3,4-tetrahydro-1,5-naphthyridine (1 g, 2.84 mmol) and diethyl malonate (0.592 g, 3.70 mmol) in N,N-dimethylformamide (10 ml) was added K₂CO₃ (0.786 g, 5.69 mmol). The reaction mixture was stirred at 100° C. for 16 hours, then quenched with water (50 ml) and 1N HCl (5 ml). The aqueous layer was extracted with EtOAc (20 mL×3). The combined organic phase was washed with brine (20 ml×3), dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc=100:1 to 10:1) to give the title compound as a yellow solid. LCMS (ESI) calculated for C₂₃H₂₈ClN₂O₄ [M+H]⁺: 431.2. found: 431.2.

Step 9—Preparation of (R and S)-ethyl 3-(1-benzyl-7-chloro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoate

A mixture of (R and S)-diethyl 2-((1-benzyl-7-chloro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)malonate (500 mg, 1.160 mmol) in DMSO (10 ml) was added LiCl (246 mg, 5.80 mmol). The reaction mixture was stirred at 170° C. for 10 h, then poured into water (100 mL) and extracted with EtOAc (50 mL×3). The organic layer was washed with brine (50 mL×3), dried over Na₂SO₄ and concentrated in vacuo. The crude product was purified by column chromatography (EtOAc:petroleum ether=0-20%) to give the title compound as a yellow solid. LCMS (ESI) calculated for C₂₀H₂₄ClN₂O₂ [M+H]⁺: 359.1. found: 359.1.

Step 10—Preparation of (R and S)-ethyl 3-(1-benzyl-7-((diphenylmethylene)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoate

A mixture of (R and S)-ethyl 3-(1-benzyl-7-chloro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoate (100 mg, 0.279 mmol) in toluene (10 mL) was added diphenylmethanimine (60.6 mg, 0.334 mmol), Pd₂(dba)₃ (25.5 mg, 0.028 mmol) and K₃PO₄ (1509 mg, 7.11 mmol). The reaction mixture was stirred at 100° C. for 16 h, then quenched with water (10 mL) and extracted with EtOAc (10 mL×3). The organic layer was washed with brine (10 mL×3), dried over Na₂SO₄ and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (EtOAc:petroleum ether=0-30%) to give the title compound as a yellow solid. LCMS (ESI) calculated for C₃₃H₃₄N₃O₂ [M+H]⁺: 504.3. found: 504.3.

Step 11—Preparation of (R and S)-ethyl 3-(7-amino-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoate

Pd/C (21.13 mg, 0.020 mmol, w/w %=10%) was added to a solution of (R and S)-ethyl 3-(1-benzyl-7-((diphenylmethylene)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoate (50 mg, 0.099 mmol) in EtOH (10 mL). The mixture was stirred under H₂ atmosphere (50 psi) at 18° C. for 16 h, then filtered. The filtrate was concentrated under vacuum to afford the crude title compound as a yellow solid, which was used without further purification. LCMS (ESI) calculated for C₁₃H₂₀N₃O₂ [M+H]⁺: 250.2. found: 250.2.

Step 12—Preparation of (S)-ethyl 3-(7-(3,3,3-trifluoro-2,2-dimethylpropanamido)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoate and (R)-ethyl 3-(7-(3,3,3-trifluoro-2,2-dimethylpropanamido)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoate

A mixture of (R and S)-ethyl 3-(7-amino-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoate (100 mg, 0.401 mmol) and 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (107 mg, 0.481 mmol) in DMSO (5 ml) was treated with concentrated HCl (19.76 mg, 0.201 mmol) and stirred at 80° C. for 5 hours. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (20 ml×3). The organic layer was washed with brine (10 mL×3), dried over Na₂SO₄ and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (EtOAc:petroleum ether=0-30%) to give an (R)- and (S)-mixture of ethyl 3-(7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoate as a yellow solid. LCMS (ESI) calculated for C₁₈H₂₅F₃N₃O₄ [M+H]⁺: 404. found: 404.

The mixture of enantiomers (Isomer 1 and Isomer 2) was resolved by SFC (Instrument: Thar SFC 350 Column: AD 250 mm*30 mm, 10 um Mobile phase: A: Supercritical CO₂, B: EtOH (0.1% NH₃H₂O), A:B=80:20 at 60 ml/min; Column Temp: 38° C.; Nozzle Pressure: 100 Bar; Nozzle Temp: 60° C.; Evaporator Temp: 25° C.; Trimmer Temp: 25° C.; Wavelength: 220 nm) to afford (R)-ethyl 3-(7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoate and (S)-ethyl 3-(7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoate as a yellow solid LCMS (ESI) calculated for C₁₈H₂₅F₃N₃O₄ [M+H]⁺: 404. found: 404.

Step 13—Preparation of (S)-ethyl 3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoate and (R)-ethyl 3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoate

To a solution of (S or R)-ethyl 3-(7-(3,3,3-trifluoro-2,2-dimethylpropanamido)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoate (Isomer 1 from Step 12, 50 mg, 0.124 mmol) in pyridine (2 mL) and THF (2 mL) was added 3-chloro-1-ethyl-1H-pyrazole-4-sulfonyl chloride (34.1 mg, 0.149 mmol). The reaction was stirred at 60° C. for 3 h, then treated with 1M HCl aqueous solution (pH ˜4) and extracted with EtOAc (10 mL×3). The combined organic layers were dried over anhydrous Na₂SO₄, and concentrated. The title compound (Isomer 1 from Step 13) was obtained by prep-TLC (SiO₂, petroleum ether:EtOAc=2:1) as a yellow solid.

The other enantiomer (Isomer 2 from Step 13) was prepared using a similar procedure as described above. Both enantiomers have the same analytical data: LCMS (ESI) calculated for C₂₃H₃₀ClF₃N₅O₆S [M+H]⁺: 596. found: 596.

Step 14—Preparation of (S)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoic acid and (R)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoic acid

To a solution (S)-ethyl 3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoate (Isomer 1 from Step 13, 30 mg, 0.050 mmol) in acetonitrile (2 mL) and water (2 mL) was added lithium hydroxide (1.205 mg, 0.050 mmol) and the reaction was warmed to 20° C. for 1 h. The reaction mixture was evaporated under vacuum and the residue purified by prep-HPLC (MeCN/water using TFA buffer) to afford the title compound (R or S)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoic acid (Isomer 1, Example 112A) as a white solid.

The other enantiomer (Isomer 2, Example 112B) was prepared using a similar procedure from Isomer 2 from Step 13. Both enantiomers have the same analytical data: LCMS (ESI) calculated for C₂₁H₂₆ClF₃N₅O₆S [M+H]⁺: 568. found: 568. ¹HNMR (400 MHz, CDCl₃) δ 8.89 (1H, s), 8.79 (1H, s), 8.59 (1H, s), 8.24 (1H, s), 4.31 (1H, d, J=12.0 Hz), 4.13 (1H, q, J=7.0 Hz), 3.45-3.50 (2H, m), 3.29 (1H, d, J=15.2 Hz), 2.76 (2H, m), 2.49 (1H, br s), 2.15 (1H, br s), 1.74-1.79 (7H, m), 1.50 (1H, d, J=7.2 Hz).

Example 113 Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl (14(4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate (Example 113)

Step 1—Preparation of 1,2,3,4-tetrahydroquinolin-7-amine

7-Nitro-1,2,3,4-tetrahydroquinoline (2 g, 11.22 mmol) and Pd/C (1.2 g) in EtOH (20 mL) were stirred under H₂ at 25° C. for 1 h, then filtrated. The filtrate was concentrated to obtain the product as black oil. LCMS (ESI) calculated for C₉H₁₃N₂ [M+H]⁺: 149. found: 149 ¹H NMR (CDCl₃ 400 MHz,) δ 6.68-6.75 (1H, m), 5.99 (1H, dd, J=2.0, 7.8 Hz), 5.78-5.86 (1H, m), 3.21-3.25 (2H, m), 2.63 (2H, t, J=6.3 Hz, 2H), 1.85-1.92 (2H, m).

Step 2—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl (1,2,3,4-tetrahydroquinolin-6-yl)carbamate

A solution of 1,2,3,4-tetrahydroquinolin-6-amine (1.2 g, 8.10 mmol) and 3-methyl-1-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-1H-imidazol-3-ium iodide (1.921 g, 8.10 mmol) in 15 mL of DMSO was stirred at 25° C. for 2 h, then quenched with H₂O and extracted 3× with EtOAc. The combined organic layers were dried and concentrated. The crude product was purified by column chromatography (petroleum ether:EtOAc=10:1) to give 1,1,1-trifluoro-2-methylpropan-2-yl (1,2,3,4-tetrahydroquinolin-6-yl)carbamate as yellow slid. LCMS (ESI) calculated for C₁₄H₁₈F₃N₂O₂ [M+H]⁺: 303. found: 303. ¹H NMR (CDCl₃ 400 MHz,) δ 6.82 (1H, d, J=8.2 Hz), 6.64 (1H, br s), 6.50 (1H, brs), 6.40 (1H, d, J=7.4 Hz), 3.22-3.28 (2H, m), 2.67 (2H, t, J=6.1 Hz, 2H), 1.89 (2H, d, J=5.8 Hz, 2H), 1.72 (6H, s).

Step 3—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl (1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate

To a solution of 1,1,1-trifluoro-2-methylpropan-2-yl (1,2,3,4-tetrahydroquinolin-7-yl)carbamate (200 mg, 0.662 mmol) and pyridine (10.5 mg, 0.13 mmol) in THF (2 mL) was added 4-fluorobenzene-1-sulfonyl chloride (28 mg, 0.14 mmol) at room temperature. The reaction mixture was stirred at 80° C. overnight, then cooled and extracted with water and EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated in vacuo. The crude product was purified by prep-HPLC (MeCN/water using TFA buffer) to give the title compound as colorless oil. LCMS (ESI) calculated for C₂₀H₂₁F₄N₂O₄S [M+H]⁺: 461. found: 461. ¹H NMR (CD₃OD, 400 MHz) δ 7.86 (brs, 1H), 7.68-7.76 (m, 2H), 7.12-7.26 (m, 3H), 6.94 (d, J=8.2 Hz, 1H), 3.77-3.85 (m, 2H), 2.41 (t, J=6.46 Hz, 2H), 1.76 (s, 6H), 1.60-1.69 (m, 2H).

Example 114 Preparation of additional 1,2,3,4-tetrahydroquinolines

The compounds in Table 33 below were prepared based on the experimental procedures described in Example 113 and elsewhere in the detailed description, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 33 Ex. Observed No. Structure Name m/z 114A

2,2,2-trifluoro-1,1- dimethylethyl {l-[(3- chloro-1-ethyl-1H-pyrazol- 4-yl)sulfonyl]-1,2,3,4- tetrahydroquinolin-7- yl}carbamate 495 (M + H)+ 114B

2,2,2-trifluoro-1,1- dimethylethyl (1-{[1-ethyl- 3-(2-hydroxyethoxy)-1H- pyrazol-4-yl]sulfonyl}- 1,2,3,4-tetrahydroquinolin- 7-yl)carbamate 521 (M + H)+ 114C

2,2,2-trifluoro-1,1- dimethylethyl {1-[(3- ethoxy-1-ethyl-1H-pyrazol- 4-yl)sulfonyl]-1,2,3,4- tetrahydroquinolin-7- yl}carbamate 505 (M + H)+ 114D

2,2,2-trifluoro-1,1- dimethylethyl (1-{[2- (trifluoromethyl)pyridin-4- yl]sulfonyl}-1,2,3,4- tetrahydroquinolin-7- yl)carbamate 512 (M + H)+

Example 115 Preparation of (R or S) and (S or R)-1,1,1-trifluoro-2-methylpropan-2-yl (3-(acetamidomethyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate (Examples 115A and 115B)

Step 1—Preparation of (2-amino-4-nitrophenyl)methanol

To a solution of 2-amino-4-nitrobenzoic acid (10 g, 54.9 mmol) in THF (150 mL), which was stirred in a 500 mL of sealed tube, was slowly added BH₃.DMS (15.64 mL, 165 mmol) dropwise at 0° C. under N₂. The resulting mixture was stirred at 90° C. for 4 h, then cooled to 0° C. and treated dropwise with MeOH (60 mL). The resulting suspension was concentrated to afford the crude titled compound as a yellow solid, which was directly used in the next step without further purification. LCMS (ESI) calculated for C₇H₉N₂O₃ [M+H]⁺: 169 found: 169. ¹HNMR (CDCl₃, 400 MHz) δ 7.54 (1H, s), 7.46 (1H, dd, J=8.0, 1.6 Hz), 7.31 (1H, d, J=8.4 Hz), 4.60 (2H, s).

Step 2—Preparation of 2-amino-4-nitrobenzaldehyde

A mixture of (2-amino-4-nitrophenyl)methanol (9 g, 53.5 mmol) and manganese (IV) oxide (93 g, 1070 mmol) in DCM (150 mL) and hexane (150 mL) was stirred at 20° C. for 1 h. The suspension was filtered and washed with DCM. The filtrate was concentrated in vacuo to give the crude titled product as a yellow solid, which was directly used in next step without further purification. ¹H-NMR (CDCl₃, 400 MHz) δ 9.95 (1H, s), 7.63 (1H, d, J=8.8 Hz), 7.47 (2H, d, J=6.0 Hz), 6.38 (2H, br s).

Step 3—Preparation of methyl 7-nitro-2-oxo-1,2-dihydroquinoline-3-carboxylate

A mixture of 2-amino-4-nitrobenzaldehyde (6.6 g, 39.7 mmol), potassium acetate (0.390 g, 3.97 mmol), dimethyl malonate (6.30 g, 47.7 mmol), and diacetoxycopper (0.361 g, 1.986 mmol) in HOAc (60 mL) was stirred at 110° C. for 48 h. Most of the solvent was removed in vacuo and the resulting precipitate was collected by filtration, washed with EtOAc and dried in vacuo to give the titled compound as a yellow solid. LCMS (ESI) calculated for C₁₁H₉N₂O₅ [M+H]⁺: 249. found: 249. ¹H-NMR (DMSO-d6, 400 MHz) δ 12.44 (1H, s), 8.60 (1H, s), 8.07 (2H, s), 7.97 (1H, s), 3.80 (3H, s).

Step 4—Preparation of (R and S)-(7-nitro-1,2,3,4-tetrahydroquinolin-3-yl)methanol

To a solution of methyl 7-nitro-2-oxo-1,2-dihydroquinoline-3-carboxylate (3 g, 12.05 mmol) in THF (200 mL) was added LiBH₄ (1.27 g, 60.24 mmol). The mixture was stirred at 40° C. for 18 h, then quenched by the careful addition of saturated NH₄Cl aqueous solution (20 mL). The biphasic mixture was stirred at 20° C. for 30 min, then extracted with EtOAc (200 mL×3). The combined organic phases were washed with brine (600 mL×2), dried over Na₂SO₄, filtered and concentrated in vacuo. Purification by silica gel column chromatography (petroleum ether/EtOAc=3:1 to 1:3) afforded the titled compound as a red solid. LCMS (ESI) calculated for C₁₀H₁₃N₂O₃ [M+H]⁺: 209. found: 209; ¹H-NMR (Methanol-d4, 400 MHz) δ 7.30 (2H, s), 7.05 (1H, d, J=7.6), 3.41-3.57 (3H, m), 3.05 (1H, t, J=10.4 Hz), 2.86 (1H, d, J=15.2 Hz), 2.54-2.58 (1H, m), 2.06 (1H, br s).

Step 5—Preparation of (R and S)-2-((7-nitro-1,2,3,4-tetrahydroquinolin-3-yl)methyl)isoindoline-1,3-dione

To a solution of (7-nitro-1,2,3,4-tetrahydroquinolin-3-yl)methanol (450 mg, 2.16 mmol) in THF (20 mL) was added DEAD (450 mg, 2.60 mmol), Ph₃P (682 mg, 2.60 mmol), and isoindoline-1,3-dione (383 mg, 2.60 mmol). The reaction was stirred at 20° C. for 16 h under N₂, then partitioned between EtOAc (20 mL) and H₂O (20 mL). The separated organic layer was washed with brine (30 mL×2) and dried over Na₂SO₄. The solvents were removed and the crude product was purified by silica gel column chromatography (petroleum ether/EtOAc=10:1 to 1:1) to afford the titled compound as a yellow solid. LCMS (ESI) calculated for C₁₈H₁₆N₃O₄ [M+H]⁺: 338. found: 338; ¹H-NMR (Methanol-d4, 400 MHz) δ 7.79-7.85 (4H, m), 7.27-7.34 (2H, m), 7.02-7.04 (1H, m), 3.70 (1H, d, J=7.2 Hz), 3.07-3.11 (2H, m), 2.83-2.91 (1H, m), 2.58-2.61 (1H, m), 2.36 (1H, br s).

Step 6—Preparation of (R)-tert-butyl (3-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate and (S)-tert-butyl (3-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate

To a solution of (R and S)-2-((7-nitro-1,2,3,4-tetrahydroquinolin-3-yl)methyl)isoindoline-1,3-dione (550 mg, 1.63 mmol) in EtOAc (20 mL) was added di-tert-butyl dicarbonate (1.07 g, 4.90 mmol) and Pd/C (55 mg, 10%). The resulting mixture was stirred at 20° C. under H₂ balloon for 18 h, then filtered, the filtrate concentrated under the reduced pressure and purified by silica gel column chromatography (petroleum ether/EtOAc=10:1 to 1:1) to afford the title compound racemate as a light yellow solid.

The racemic mixture was resolved by chiral SFC method (Pak AS, 10 μm, Daicel Chemical Industries, Ltd 250×30 mm I.D.; Mobile phase: A: Supercritical CO₂, B:EtOH (contained 0.1% NH₃H₂O), A:B=50:50 at 80 mL/min) to afford the faster eluent (Peak 1 from Step 6) and the slower eluent (Peak 2 from Step 6) both as yellow oils. Both enantiomers have the same analytical data: LCMS (ESI) calculated for C₂₃H₂₆N₃O₄ [M+H]⁺: 408. found: 408; ¹H-NMR (CDCl₃, 400 MHz) δ 7.84-7.86 (2H, m), 7.72-7.74 (2H, m), 6.77-6.83 (2H, m), 6.38-6.40 (2H, m), 3.70 (2H, d, J=6.4 Hz), 3.30 (1H, d, J=10.8 Hz), 3.05 (1H, t, J=10.0 Hz), 2.79 (1H, dd, J=12.0, 4.0 Hz), 2.50-2.57 (1H, m), 1.49 (9H, s).

Step 7—Preparation of (R)-tert-butyl(3-((1,3-dioxoisoindolin-2-yl)methyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate and (S)-tert-butyl(3-((1,3-dioxoisoindolin-2-yl)methyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate

To a solution of (R or S)-tert-butyl (3-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate (Peak 1 from Step 6, 120 mg, 0.290 mmol) in THF (3 mL) were added pyridine (3 mL) and 4-fluoro-3-methoxybenzene-1-sulfonyl chloride (132 mg, 0.590 mmol) at 20° C. under N₂. The resulting mixture was stirred at 50° C. for 18 h, then poured into water. The aqueous layer was extracted with ethyl acetate (20 mL×3) and the combined organic layers washed with brine (30 mL×2), dried over sodium sulfate and concentrated. The crude product was purified by prep-TLC (petroleum ether/EtOAc=1:1) to afford the titled compound (Peak 1 from Step 7) as a yellow oil.

The other enantiomer (Peak 2 from Step 7) was prepared using a similar procedure as described above from Peak 2 from Step 6. Both enantiomers have the same analytical data: LCMS (ESI) calculated for C₂₆H₂₃FN₃O₇S [M+H-tBu]⁺: 540. found: 540.1; ¹H-NMR (CDCl₃, 400 MHz) δ 7.86-7.89 (2H, m), 7.76-7.78 (2H, m), 7.67 (1H, s), 7.57-7.60 (1H, m), 3.73 (3H, s), 3.56 (2H, d, J=6.8 Hz), 3.17 (1H, t, J=12.4 Hz), 2.55 (1H, dd, J=16.8, 5.2 Hz), 2.17-2.25 (2H, m), 2.01-2.05 (1H, m), 1.49 (9H, s).

Step 8—Preparation of (R)-tert-butyl (3-(aminomethyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate and (S)-tert-butyl (3-(aminomethyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate

A solution of (R or S)-tert-butyl tert-butyl (3-((1,3-dioxoisoindolin-2-yl)methyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate (Peak 1 from Step 7, 60 mg, 0.10 mmol) in EtOH (15 mL) was treated with N₂H₄—H₂O (0.5 mL) for 2 h at 85° C., then cooled to room temperature and filtered. The filtrate was concentrated, purified by silica gel chromatography (EtOAc/MeOH=5:1) to afford the title compound as a light yellow solid.

The other enantiomer (Peak 2 from Step 8) was prepared using a similar procedure as described above from Peak 2 from Step 7. Both enantiomers have the same analytical data: LCMS (ESI) calculated for C₂₂H₂₉FN₃O₅S [M+H]⁺: 466. found: 466; ¹H-NMR (CDCl₃, 400 MHz) δ 7.72 (1H, s), 7.47 (1H, s), 7.32 (1H, d, J=6.4 Hz), 7.11 (1H, t, J=8.8 Hz), 6.86 (1H, dd, J=25.2, 8.0 Hz), 4.32 (1H, d, J=10.8 Hz), 3.78 (3H, s), 3.48 (2H, s), 3.37 (1H, br s), 3.09 (2H, br s), 2.69 (1H, d, J=14.0 Hz), 2.46 (1H, br s), 2.27 (1H, br s), 1.49 (9H, s).

Step 9—Preparation of (R)-tert-butyl(3-(acetamidomethyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate and (S)-tert-butyl(3-(acetamidomethyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate

To a solution of (R or S)-tert-butyl (3-(aminomethyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate (Peak 1 from Step 8, 40 mg, 0.086 mmol) in 3 mL of methylene chloride is first added TEA (0.036 mL, 0.258 mmol) and then slowly treated with acetyl chloride (10.12 mg, 0.129 mmol). The reaction mixture is stirred at 20° C. for two hours, then quenched with water (0.5 mL). The separated organic layer was dried over Na₂SO₄, filtered and concentrated. The crude product was purified by prep-TLC (petroleum ether/EtOAc=1:2) to afford the title compound (Peak 1 from Step 9) as a light yellow solid.

The other enantiomer (Peak 2 from Step 9) was prepared using a similar procedure as described above from Peak 2 from Step 8. Both enantiomers have the same analytical data: LCMS (ESI) calculated for C₂₄H₃₁FN₃O₆S [M+H]⁺: 508.2. found: 508.2; ¹H-NMR (CDCl₃, 400 MHz) δ 7.73 (1H, s), 7.33-7.35 (2H, m), 7.15-7.18 (1H, m), 7.06-7.08 (1H, m), 6.95 (1H, d, J=8.8 Hz), 6.61 (1H, br s), 6.06 (1H, br s), 3.91 (1H, dd, J=13.2, 2.8 Hz), 3.85 (3H, s), 3.47-3.51 (1H, m), 3.34-3.36 (1H, m), 3.05-3.09 (1H, m), 2.66 (1H, dd, J=16.4, 6.0 Hz), 2.22-2.27 (1H, m), 2.02 (3H, s), 1.51 (9H, s).

Step 10—Preparation of (R)—N-((7-amino-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acetamide and (S)—N-((7-amino-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acetamide

To a solution of (R or S)-tert-butyl (3-(acetamidomethyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate (Peak 1 from Step 9, 30 mg, 0.059 mmol) in EtOAc (1 mL) was added HCl (2 mL, 4 M in EtOAc). The reaction was stirred at 20° C. for 2 h, then concentrated and purified by prep-TLC (petroleum ether/EtOAc=1:2) to afford the titled compound (Peak 1 from Step 10) as a light yellow solid.

The other enantiomer (Peak 2 from Step 10) was prepared using a similar procedure as described above from Peak 2 from Step 9. Both enantiomers have the same analytical data: LCMS (ESI) calculated for C₁₉H₂₃FN₃O₄S [M+H]⁺: 408.1. found: 408.1; ¹H-NMR (CDCl₃, 400 MHz) δ 7.26-7.28 (1H, m), 7.13-7.16 (2H, m), 7.06 (1H, d, J=2.4 Hz), 6.81 (1H, d, J=8.0 Hz), 6.46 (1H, d, J=2.0 Hz), 5.76 (1H, br s), 4.00 (1H, dd, J=13.6, 4.0 Hz), 3.78 (3H, s), 3.26-3.35 (2H, m), 3.02-3.08 (1H, m), 2.52 (1H, dd, J=16.0, 6.4 Hz), 2.66 (1H, dd, J=16.4, 6.0 Hz), 2.08-2.18 (1H, m), 2.01 (3H, s).

Step 11—Preparation of (R)-1,1,1-trifluoro-2-methylpropan-2-yl (3-(acetamidomethyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate and (S)-1,1,1-trifluoro-2-methylpropan-2-yl (3-(acetamidomethyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate

To a solution of (R or S)—N-((7-amino-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acetamide (Peak 1 from Step 10, 20 mg, 0.049 mmol) in DMSO (5 mL) was added 3-methyl-1-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-1H-imidazol-3-ium iodide (24.3 mg, 0.098 mmol). The resulting mixture was stirred at 20° C. for 1 h, then extracted with EtOAc (5 mL×3), washed with brine (5 mL×2), dried over Na₂SO₄ and purified by prep-HPLC to afford the title compound (Peak 1 from Step 11, Example 115A) as a white solid.

The other enantiomer (Peak 2 from Step 11, Example 115B) was prepared using a similar procedure as described above from Peak 2 from Step 10. Both enantiomers have the same analytical data: LCMS (ESI) calculated for C₂₄H₂₈F₄N₃O₆S [M+H]⁺: 562.1. found: 562.1; ¹H-NMR (CDCl₃, 400 MHz) δ 7.75 (1H, s), 7.39 (2H, br s), 7.19 (1H, t, J=10.4 Hz), 6.68 (1H, s), 6.26 (1H, s), 3.89 (3H, s), 3.82-3.86 (1H, m), 3.64-3.67 (1H, m), 3.44-3.48 (1H, m), 3.09-3.11 (1H, m), 2.73-2.78 (2H, m), 2.33 (1H, dd, J=16.8, 6.4 Hz), 2.10 (3H, s), 1.75 (6H, d, J=4.4 Hz).

Example 116 Preparation of (R)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic acid and (S)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic acid (Examples 116A and 116B)

Step 1—Preparation of 7-nitroquinoline

To a solution of 7-nitro-1,2,3,4-tetrahydroquinoline (8 g, 44.9 mmol) in DCM (400 mL) was added 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (21 g, 93 mmol). The mixture was stirred for 1 hour at 60° C. The reaction mixture was poured into water (500 mL), extracted with dichloromethane (200 mL×3). The combined organic phase was dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash silica gel chromatography (SiO₂, PE:EtOAc=5:1 to 1:1) to give 7-nitroquinoline as a yellow solid.

Step 2—Preparation of 3-bromo-7-nitroquinoline

To a solution of 7-nitroquinoline (3 g, 17.23 mmol) in AcOH (50 mL) was added 1-bromopyrrolidine-2,5-dione (4.4 g, 24.72 mmol) under N₂. The mixture was stirred for 4 hours at 140° C. The reaction mixture was poured into water (200 mL), extracted with ethyl acetate (100 mL×3). The combined organic phase was dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash silica gel chromatography (SiO₂, petroleum ether:EtOAc=100:1 to 5:1) to give 3-bromo-7-nitroquinoline as a yellow solid.

Step 3—Preparation of (E)-methyl 3-(7-nitroquinolin-3-yl)acrylate

To a solution of 3-bromo-7-nitroquinoline (2 g, 7.90 mmol), potassium phosphate (3.36 g, 15.81 mmol), methyl acrylate (0.680 g, 7.90 mmol) in DMA (15 mL) and water (3 mL) was added Pd(PPh₃)₄ (0.539 g, 0.790 mmol) under N₂. The mixture was stirred at 90° C. for 16 hours under N₂. The reaction was then diluted with EtOAc (20 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic phase was dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash silica gel chromatography (SiO₂, petroleum ether:EtOAc=20:1 to 3:1) to give (E)-methyl 3-(7-nitroquinolin-3-yl)acrylate as a black solid. ¹H NMR (400 MHz, CDCl₃) δ 3.63 (s, 3H), 6.57 (d, J=16.4 Hz, 1H), 7.63 (d, J=16.4 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H), 8.12 (s, 1H), 8.21 (s, 1H), 8.74 (br. s., 1H), 8.98-9.05 (m, 1H), 9.02 (s, 1H).

Step 4—Preparation (S and R)-tert-butyl 7-((tert-butoxycarbonyl)amino)-3-(3-methoxy-3-oxopropyl)-3,4-dihydroquinoline-1(2H)-carboxylate

To a solution of (E)-methyl 3-(7-nitroquinolin-3-yl)acrylate (2 g, 7.75 mmol), di-tert-butyl dicarbonate (3.38 g, 15.49 mmol) in MeOH (300 mL) was added Pd/C (0.412 g, 3.87 mmol) under N₂. The suspension was degassed under vacuum and purged with H₂ several times. The mixture was stirred under H₂ (50 psi) at 25° C. for 16 hours. The suspension was filtered through a pad of CELITE and the filter cake was washed with MeOH (100 mL×3). The combined filtrates were concentrated to dryness. The residue was purified by flash silica gel chromatography (SiO₂, petroleum ether:EtOAc=100:1 to 5:1) to give the title compound as a brown oil.

Step 5—Preparation of (S and R)-methyl 3-(7-amino-1,2,3,4-tetrahydroquinolin-3-yl)propanoate

To a mixture of (S and R)-tert-butyl 7-((tert-butoxycarbonyl)amino)-3-(3-methoxy-3-oxopropyl)-3,4-dihydroquinoline-1(2H)-carboxylate (1.2 g, 2.76 mmol) in DCM (10.0 mL) was added dropwise TFA (5.0 mL) at 0° C. The reaction mixture was stirred at 25° C. for 2 hours. Water (10 mL) was added and the mixture was adjusted to pH=9 with statured aqueous Na₂CO₃ solution, then extracted with DCM (20 mL×3). The combined organic phase was dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash silica gel chromatography (SiO₂, petroleum ether:EtOAc=10:1 to 1:1, 0.1% Et₃N) to give the title compound as brown oil. LCMS (ESI) calculated for C₁₃H₁₉N₂O₂ (M+H)⁺: 235. found: 235.2.

Step 6—Preparation of (R)-methyl 3-(7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoate and (S)-methyl 3-(7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoate

To a mixture of (S and R)-methyl 3-(7-amino-1,2,3,4-tetrahydroquinolin-3-yl)propanoate (290 mg, 1.238 mmol) in DMSO (5.0 mL) was added 3-methyl-1-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-1H-imidazol-3-ium iodide (451 mg, 1.238 mmol). The reaction mixture was stirred at 25° C. for 30 minutes. The resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layers were separated, combined, dried over Na₂SO₄, filtered and concentrated in vacuo to give (S and R)-methyl 3-(7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoate as a brown oil. LCMS (ESI) calculated for C₁₈H₂₄F₃N₂O₄ [M+H]⁺: 389. found: 389.2.

The product was resolved by SFC (Column: Chiralcel OD-3 150×4.6 mm I.D., 3 um Mobile phase: methanol (0.05% DEA) in CO₂ from 5% to 40% Flow rate: 2.5 mL/min Wavelength: 220 nm to afford Isomer 1 (210 mg, brown oil; rT=5.2 min), Isomer 2 (206 mg, brown oil; rT=7.3 min).

Step 7. Preparation of (R)-3-(7-((((1,1,1-trifluoro-2-methylpropan-2-yl) oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic acid and (S)-3-(7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic acid

To a solution of (S or R)-methyl 3-(7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoate (Isomer 1 from Step 6, 100 mg, 0.257 mmol) in 1,4-dioxane (2.0 mL) was added LiOH (37 mg, 1.545 mmol) and water (2.0 mL). The reaction mixture was stirred at 25° C. for 2 h, then quenched with hydrochloric acid (1 M, 5 mL). The resulting mixture was extracted with ethyl acetate (3×5 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the title compound (Isomer 1 from Step 7) as a yellow solid, which was used directly in the next step without further purification.

The other enantiomer (Isomer 2 from Step 7) was prepared using a similar procedure from Isomer 2 from Step 6 as described above. Both enantiomers have the same analytical data: LCMS (ESI) calculated for C₁₇H₂₂F₃N₂O₄ [M+H]⁺: 375. found: 375.

Step 8—Preparation of (R)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic acid and (S)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic acid

To a mixture of (R or S)-3-(7-((((1,1,1-trifluoro-2-methylpropan-2-yl) oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic acid (Isomer 1 from Step 7; 30 mg, 0.080 mmol) in tetrahydrofuran (0.5 mL) was added 3-chloro-1-ethyl-1H-pyrazole-4-sulfonyl chloride (46 mg, 0.201 mmol) and pyridine (0.5 mL). The reaction mixture was stirred at 25° C. for 2 h, diluted with water (3 mL) and extracted with ethyl acetate (3 mL×3). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by prep-HPLC (MeCN/water using TFA buffer) to afford the title compound (Isomer 1, Example 116A) as a white solid.

The other enantiomer (Isomer 2, Example 116B) was prepared from Isomer 2 from Step 7 using a similar procedure as described above. Both enantiomers have the same analytical data: LCMS (ESI) calculated for C₂₂H₂₇ClF₃N₄O₆S [M+H]⁺: 567. found: 567. ¹H NMR (400 MHz, CDCl₃) δ 8.06 (1H, s), 7.85 (1H, s), 6.99 (1H, d, J=8.2 Hz), 6.87 (1H, d, J=7.4 Hz), 6.67 (1H, br), 4.30 (1H, d, J=11.0 Hz), 3.10 (2H, q, J=7.0 Hz), 3.28-3.40 (1H, m), 2.82 (1H, dd, J=16.2, 4.6 Hz), 2.50 (2H, t, J=7.4 Hz), 2.32-2.44 (1H, m), 1.94-2.06 (2H, m), 1.78 (6H, s), 1.60-1.70 (1H, m), 1.47 (3H, t, J=7.2 Hz).

Example 117 Preparation of Additional 1,2,3,4-Tetrahydroquinolin-3-yl)propanoic Acids

The compounds in Table 34 were prepared based on the experimental procedures described in Example 116, and can be achieved by one of skill in the art in light of the present disclosure.

TABLE 34 Ex. Observed No. Structure Name m/z 117A

(R or S)-3-(7-((((1,1,1- trifluoro-2-methylpropan-2- yl)oxy)carbonyl)amino)-1- ((5-(trifluoromethyl)pyridin- 3-yl)sulfonyl)-1,2,3,4- tetrahydroquinolin-3- yl)propanoic acid 584 [M + H]+ 117B

(R or S)-3-(1-((4-fluoro-3- methoxyphenyl)sulfonyl)-7- ((((1,1,1-trifluoro-2- methylpropan-2- yl)oxy)carbonyl)amino)- 1,2,3,4-tetrahydroquinolin-3- yl)propanoic acid 563 [M + H]+ 117C

(R or S)-3-(7-((((1,1,1- trifluoro-2-methylpropan-2- yl)oxy)carbonyl)amino)-1- ((5-(trifluoromethyl)pyridin- 3-yl)sulfonyl)-1,2,3,4- tetrahydroquinolin-3- yl)propanoic acid 584 [M + H]+ 117D

(R or S)-3-(1-((4-fluoro-3- methoxyphenyl)sulfonyl)-7- ((((1,1,1-trifluoro-2- methylpropan-2- yl)oxy)carbonyl)amino)- 1,2,3,4-tetrahydroquinolin-3- yl)propanoic acid 563 [M + H]+

Example 118 Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl (5-((3-chloro-1-ethyl-1-pyrazol-4-yl)sulfonyl)-8-oxo-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate Example 118

Step 1—Preparation of tert-butyl 7-nitro-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate

A solution of tert-butyl 3-oxopiperidine-1-carboxylate (6 g, 30.1 mmol) and 1-methyl-3,5-dinitropyridin-2(1H)-one (7.20 g, 36.1 mmol) in methanolic ammonia (1 M, 60 ml) was irradiated at 90° C. in a sealed vial for 45 min. The mixture was then concentrated and redissolved in CH₂Cl₂ (110 mL), the organics washed with saturated aqueous NaHCO₃ (100 ml) and water (100 mL), dried over Na₂SO₄, and evaporated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=15:1-4:1) to give the title product as a light yellow solid. LCMS (ESI) calculated for C₁₃H₁₈N₃O₄ [M+H]⁺: 280.1. found: 280.2; ¹H-NMR (CDCl₃, 400 MHz) δ 8.97 (2H, s), 3.79-3.76 (2H, m), 3.06-3.02 (2H, m), 2.06-2.00 (2H, m), 1.54 (9H, s).

Step 2—Preparation of 5-(tert-butoxycarbonyl)-3-nitro-5,6,7,8-tetrahydro-1,5-naphthyridine 1-oxide

A mixture of tert-butyl 7-nitro-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate (500 mg, 1.790 mmol) and m-CPBA (618 mg, 3.58 mmol) in CH₂Cl₂ (15 mL) was stirred at 20° C. for 18 hours. Additional CH₂Cl₂ (10 mL) was added to dissolve the solids and the organics washed with saturated sodium bicarbonate, water, brine and dried over sodium sulfate. The solvent was removed to give the crude title compound as a dark yellow solid, which was used directly in the next step. LCMS (ESI) calculated for C₁₃H₁₈N₃O₅ [M+H]⁺: 296.1. found: 296.1.

Step 3—Preparation of tert-butyl 4-acetoxy-7-nitro-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate

A mixture of 5-(tert-butoxycarbonyl)-3-nitro-5,6,7,8-tetrahydro-1,5-naphthyridine 1-oxide (503 mg, 1.703 mmol), Ac₂O (6 ml, 63.6 mmol) and toluene (6 mL) was heated to reflux for 5 hours under nitrogen. The reaction was concentrated under vacuum and azeotroped three times with toluene to give the crude title compound as black oil. LCMS (ESI) calculated for C₁₅H₂₀N₃O₆ [M+H]⁺: 338.1. found: 338.1; ¹H-NMR (CDCl₃, 400 MHz) δ 9.19 (1H, s), 9.07 (1H, d, J=2.0 Hz), 6.04-6.01 (1H, m), 4.17-4.12 (2H, m), 3.69-3.63 (2H, m), 2.15 (3H, s), 1.58 (9H, s).

Step 4—Preparation of tert-butyl 4-hydroxy-7-nitro-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate

A mixture of tert-butyl 4-acetoxy-7-nitro-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate (592 mg, 1.755 mmol) and 2N potassium carbonate (2.63 ml, 5.26 mmol) in MeOH (8 ml) and THF (8 mL) was stirred at 20° C. for 15 h. The organic solvents were removed under vacuum and the aqueous residue extracted with ethyl acetate (3×12 mL). The organic layer was washed with brine (8 mL) and dried over sodium sulfate. The solvent was removed and the crude product was purified by column chromatography (petroleum ether:ethyl acetate=3:1) to give the titled compound as a yellow oil. ¹H-NMR (CDCl₃, 400 MHz) δ 9.11 (1H, s), 8.96 (1H, d, J=1.6 Hz), 4.71-4.67 (1H, m), 4.11 (1H, s), 3.90-3.85 (1H, m), 3.74-3.68 (1H, m), 2.41-2.36 (1H, m), 1.86-1.80 (1H, m), 1.51 (9H, s).

Step 5—Preparation of tert-butyl 7-nitro-4-oxo-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate

A mixture of tert-butyl 4-hydroxy-7-nitro-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate (291 mg, 0.985 mmol) and manganese (IV) oxide (857 mg, 9.85 mmol) in CH₂Cl₂ (10 mL) was stirred at 25° C. for 18 hours. Additional CH₂Cl₂ (15 mL) was added, the solution filtered and the filtrate concentrated under vacuum. The residue was purified by column chromatography (petroleum ether:ethyl acetate=3:1) to give the title compound as a yellow solid. ¹H-NMR (CDCl₃, 400 MHz) δ 9.23 (2H, s), 4.29 (2H, t, J=6.4 Hz), 3.02-2.98 (2H, m), 1.61 (9H, s).

Step 6—Preparation of tert-butyl 4,4-difluoro-7-nitro-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate

To a solution of tert-butyl 7-nitro-4-oxo-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate (184 mg, 0.627 mmol) in CH₂Cl₂ (8 mL) was added DAST (2 mL, 15.14 mmol) at −20° C. under nitrogen. The reaction was allowed to warm up to 20° C. slowly and stirred at 20° C. for 18 h. The resulting mixture was diluted with CH₂Cl₂ (15 mL), poured into cooled sat. NaHCO₃ (10 mL) and extracted with CH₂Cl₂ (3×15 mL). The combined organic layers were washed with brine (8 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=9:1) to afford the title compound as yellow solid. ¹H-NMR (CDCl₃, 400 MHz) δ 9.27 (1H, s), 9.17 (1H, d, J=2.0 Hz), 4.10-4.05 (2H, m), 2.60-2.51 (2H, m), 1.58 (9H, s).

Step 7—Preparation of tert-butyl 7-amino-4,4-difluoro-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate

To a solution of tert-butyl 4,4-difluoro-7-nitro-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate (120 mg, 0.381 mmol) in EtOAc (8 mL) was added nickel (11.17 mg, 0.190 mmol) in one portion at 25° C. under nitrogen. The reaction was stirred at 25° C. under H₂ (15 psi) for 4 hours, then filtered and evaporated to afford crude tert-butyl 7-amino-4,4-difluoro-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate as a yellow oil. LCMS (ESI) calculated for C₁₃H₁₈F₂N₃O₂ [M+H]⁺: 286.1. found: 286.3.

Step 8—Preparation of tert-butyl 4,4-difluoro-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate

To a solution of tert-butyl 7-amino-4,4-difluoro-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate (65 mg, 0.228 mmol) and 3-methyl-1-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-1H-imidazol-3-ium iodide (83 mg, 0.228 mmol) in DMSO (2 mL) was stirred at 20° C. under nitrogen for 24 hours. The reaction was diluted with EtOAc (10 mL) and washed with brine (3×6 mL). The organic layer was dried over Na₂SO₄, filtered, and the filtrate was concentrated in vacuum to give crude title compound as yellow solid. LCMS (ESI) calculated for C₁₈H₂₃F₅N₃O₄ [M+H]⁺: 440.2. found: 440.1.

Step 9—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl (8-oxo-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

To a solution of tert-butyl 4,4-difluoro-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate (43 mg, 0.098 mmol) in EtOAc (1 mL) was added a solution of HCl in EtOAc (3 ml, 4 N). The reaction was stirred at 20° C. for 2 h, then concentrated to give the crude title compound as yellow oil. LCMS (ESI) calculated for C₁₃H₁₅F₃N₃O₃ [M+H]⁺: 318.1. found: 318.0.

Step 10—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl (5-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-8-oxo-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

To a mixture of 1,1,1-trifluoro-2-methylpropan-2-yl (8-oxo-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate (10 mg, 0.032 mmol) in THF (1 mL) was added 3-chloro-1-ethyl-1H-pyrazole-4-sulfonyl chloride (14.4 mg, 0.063 mmol) and pyridine (1 mL). The reaction was stirred at 25° C. for 16 hours, then diluted with water (3 mL) and extracted with ethyl acetate (3×6 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. The crude product was purified by prep-HPLC (MeCN/water using TFA buffer) to afford the title compound as white solid. LCMS (ESI) calculated for C₁₈H₂₀ClF₃N₅O₅S [M+H]⁺: 510.1. found: 510.0; ¹H-NMR (CDCl₃, 400 MHz) δ 8.57 (1H, s), 8.14 (1H, s), 7.46 (1H, s), 4.34 (s, 2H), 4.08 (2H, d, J=7.2 Hz), 2.90 (2H, s), 1.71 (6H, s), 1.46 (3H, s).

Example 119 Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl (1-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-4-oxo-1,2,3,4-tetrahydroquinolin-7-yl)carbamate (Example 119)

Step 1—Preparation of 1,2,3,4-tetrahydroquinolin-7-amine

7-nitro-1,2,3,4-tetrahydroquinoline (2 g, 11.22 mmol) and Pd/C (1.2 g) in EtOH (20 mL) were stirred under H₂ at 25° C. for 1 h, then filtered. The filtrate was concentrated to obtain the crude product as black oil, which was used in the next step without further purification. LCMS (ESI) calculated for C₉H₁₃N₂ [M+H]⁺: 149. found: 149 ¹H NMR (CDCl₃ 400 MHz,) δ 6.68-6.75 (1H, m), 5.99 (1H, dd, J=2.0, 7.8 Hz), 5.78-5.86 (1H, m), 3.21-3.25 (2H, m), 2.63 (2H, t, J=6.3 Hz, 2H), 1.85-1.92 (2H, m).

Step 2—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl (1,2,3,4-tetrahydroquinolin-6-yl)carbamate

To a solution of 1,2,3,4-tetrahydroquinolin-6-amine (1.2 g, 8.10 mmol) and 3-methyl-1-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-1H-imidazol-3-ium iodide (1.921 g, 8.10 mmol) in 15 mL of DMSO was stirred at 25° C. for 2 h. The reaction was quenched with H₂O and extracted with EtOAc. The organic layer was dried, concentrated and the crude product was purified by column chromatography (petroleum ether:EtOAc=10:1) to give 1,1,1-trifluoro-2-methylpropan-2-yl (1,2,3,4-tetrahydroquinolin-6-yl)carbamate as yellow solid. LCMS (ESI) calculated for C₁₄H₁₇F₃N₂O₂ [M+H]⁺: 303. found: 303 ¹H NMR (CDCl₃ 400 MHz) δ 6.82 (1H, d, J=8.2 Hz), 6.64 (1H, br s), 6.50 (1H, br s), 6.40 (1H, d, J=7.4 Hz), 3.22-3.28 (2H, m), 2.67 (2H, t, J=6.1 Hz, 2H), 1.89 (2H, d, J=5.8 Hz, 2H), 1.72 (6H, s).

Step 3-Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl(1-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate

To a solution of 1,1,1-trifluoro-2-methylpropan-2-yl (1,2,3,4-tetrahydroquinolin-7-yl)carbamate (200 mg, 0.662 mmol) and pyridine (105 mg, 1.32 mmol) in THF (2 mL) was added 4-fluoro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (347 mg, 1.323 mmol) and the reaction mixture was stirred at 80° C. overnight, then extracted with EtOAc and water. The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by prep-TLC (petroleum ether:EtOAc=10:1) to give crude title product as colorless oil, which was taken forward without further purification. ¹H NMR (CDCl₃, 400 MHz) δ 7.94 (1H, d, J=5.1 Hz), 7.80-7.66 (2H, m), 7.16 (1H, s), 7.12-7.04 (1H, m), 6.91 (1H, d, J=8.2 Hz), 6.60 (1H, brs), 3.81-3.72 (2H, m), 2.42 (2H, t, J=6.5 Hz), 1.70 (6H, s), 1.67-1.61 (2H, m).

Step 4-Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl(1-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-4-oxo-1,2,3,4-tetrahydroquinolin-7-yl)carbamate

To a solution of 1,1,1-trifluoro-2-methylpropan-2-yl(1-((4-fluoro-3-(trifluromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate (200 mg, 0.378 mmol) in n-butanol (5 mL) was added solution of KMnO₄ (269 mg, 1.703 mmol) and KH₂PO₄ (232 mg, 1.703 mmol) solution (dissolved in 1 mL H₂O) in portions at 0° C. The reaction was stirred at 15° C. overnight, then quenched with H₂O and extracted with EtOAc. The organic layer was dried and concentrated to give 1,1,1-trifluoro-2-methylpropan-2-yl (1-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-4-oxo-1,2,3,4-tetrahydroquinolin-7-yl)carbamate as colorless oil. LCMS (ESI) calculated for C₂₁H₁₈F₇N₂O₅S [M+H]⁺: 543.1. found: 543.0.

Example 120 Preparation of (R or S)-1,1,1-trifluoro-2-methylpropan-2-yl (6-methyl-8-oxo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate (Example 120)

Step 1—Preparation of 2,5-dibromopyridin-3-amine

To a solution of 2,5-dibromo-3-nitropyridine (13.00 g, 46.1 mmol) in acetone (150 mL) was added ammonium chloride (24.67 g, 461 mmol) and zinc dust (15.08 g, 231 mmol) and the resulting mixture was stirred at room temperature for 5 h under N₂. Water (100 mL) was next added and the aqueous layer was extracted with EtOAc (3×200 mL). The combined organic layers were concentrated in vacuo and the crude product was purified by flash chromatography (0-30% EtOAc in petroleum ether) to afford the title compound as a white solid. ¹H NMR (400 MHz, MeOD) δ 7.67 (d, J=2.0 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H).

Step 2. Preparation of N-(2,5-dibromopyridin-3-yl)-3-(trifluoromethyl)-N-((3-(trifluoromethyl)phenyl)sulfonyl)benzenesulfonamide

To a solution of 2,5-dibromopyridin-3-amine (1.00 g, 3.97 mmol) in THF (15 mL) and pyridine (15 mL) was added 3-(trifluoromethyl)benzene-1-sulfonyl chloride (1.16 g, 4.74 mmol) and the resulting mixture was stirred at room temperature for 18 h under N₂. The reaction was quenched with aqueous NH₄Cl (20 mL) and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were concentrated in vacuo to afford the title compound as yellow solid. LCMS (ESI) calculated for C₁₉H₁₁Br₂F₆N₂O₄S₂ [M+H]⁺: 666.8. found: 668.7.

Step 3—Preparation of N-(2,5-dibromopyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide

To a solution of N-(2,5-dibromopyridin-3-yl)-3-(trifluoromethyl)-N-((3-(trifluoromethyl)phenyl)sulfonyl)benzenesulfonamide (10.0 g, 14.97 mmol) in MeOH (30 mL) was added KOH (4.20 g, 74.8 mmol) in water (10 mL). The resulting mixture was stirred at 60° C. for 2 h under N₂. The solution was adjusted to pH=4 with 1 M HCl and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were concentrated in vacuo and the crude product was purified by flash chromatography (0-50% EtOAc in petroleum ether) to afford the title compound as yellow oil. ¹H NMR (400 MHz, MeOD) 8.29 (d, J=1.6 Hz, 1H), 8.00-8.11 (m, 2H), 7.95 (d, J=7.4 Hz, 2H), 7.66-7.78 (m, 1H).

Step 4-Preparation of N-(2,5-dibromopyridin-3-yl)-N-(pent-4-en-2-yl)-3-(trifluoromethyl) benzenesulfonamide

To a solution of N-(2,5-dibromopyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide (5.00 g, 10.87 mmol) in THF (50 mL) was added triphenylphosphine (3.42 g, 13.04 mmol), pent-4-en-2-ol (1.12 g, 13.00 mmol) and (E)-diethyl diazene-1,2-dicarboxylate (2.27 g, 13.03 mmol) at room temperature. The resulting mixture was heated to 60° C. for 36 h, then treated with 100 mL of water. The aqueous layer was extracted with EtOAc (3×100 mL) and the combined organic layers were concentrated in vacuo. The crude product was purified by flash chromatography (0-20% EtOAc in petroleum ether) to afford the title compound as a white solid. LCMS (ESI) calculated for C₁₇H₁₆Br₂F₃N₂O₂S [M+H]⁺: 526.9. found: 529.0.

Step 5—Preparation of 7-bromo-2-methyl-4-methylene-1-((3-(trifluoromethyl)phenyl) sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridine

To a solution of N-(2,5-dibromopyridin-3-yl)-N-(pent-4-en-2-yl)-3-(trifluoromethyl)benzenesulfonamide (500 mg, 0.95 mmol) in 1,4-dioxane (20 mL) was added Cs₂CO₃ (617 mg, 1.89 mmol), followed by Pd₂(dba)₃ (43 mg, 0.047 mmol). The resulting mixture was stirred at 80° C. for 18 h under N₂, then concentrated in vacuo. The crude product was purified by flash chromatography (0-20% EtOAc in petroleum ether) to afford the title compound as a white solid. LCMS (ESI) calculated for C₁₇H₁₅BrF₃N₂O₂S [M+H]⁺: 447.0. found: 449.0, ¹H NMR (400 MHz, MeOD) 8.51 (br s, 1H), 7.94-8.09 (m, 3H), 7.72-7.85 (m, 2H), 5.52-5.75 (m, 1H), 4.93-5.09 (m, 2H), 4.15-4.34 (m, 1H), 2.71-2.82 (m, 1H), 2.24-2.34 (m, 1H), 2.03-2.16 (m, 1H), 1.22 (d, J=6.6 Hz, 2H), 1.15 (d, J=6.6 Hz, 1H).

Step 6—Preparation of 7-bromo-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3-dihydro-1,5-naphthyridin-4(1H)-one

To a solution of 7-bromo-2-methyl-4-methylene-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridine (400 mg, 0.89 mmol) in MeOH (20 mL) was added sodium periodate (574 mg, 2.68 mmol), followed by aqueous osmium tetroxide (0.056 mL, 0.18 mmol) and water (10 mL). The resulting mixture was stirred at room temperature for 3 h under N₂, then concentrated in vacuo. The crude product was purified by flash chromatography (0-20% EtOAc in petroleum ether) to afford the title compound as a white solid. LCMS (ESI) calculated for C₁₆H₁₃BrF₃N₂O₃S [M+H]⁺: 449.0. found: 449.1.

Step 7—Preparation of (R)-tert-butyl (6-methyl-8-oxo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate and (S)-tert-butyl (6-methyl-8-oxo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

To a solution of 7-bromo-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3-dihydro-1,5-naphthyridin-4(1H)-one (120 mg, 0.27 mmol) in 1,4-Dioxane (2 mL) was added Cs₂CO₃ (174 mg, 0.53 mmol), followed by tert-butyl carbamate (62 mg, 0.53 mmol) and (RuPhos) palladium(II) phenethylamine chloride (10 mg, 0.014 mmol). The resulting mixture was stirred at 90° C. for 18 h under N₂, then filtered and washed with EtOAc (20 mL). The combined organics were removed in vacuo and the crude product was purified by prep-HPLC (MeCN/water using TFA buffer) to afford the title racemate as a white solid.

The above racemic mixture was separated by chiral SFC (Column: IC 250×4.6 mm I.D., 5 um; Mobile phase: iso-propanol (0.05% DEA) in CO₂ from 5% to 40%; Flow rate: 2.5 mL/min; Wavelength: 220 nm) to afford two enantiomers (faster eluent, Isomer 1 from Step 7 and slower eluent, Isomer 2 from Step 7), which have the same analytical data: LCMS (ESI) calculated for C₂₁H₂₃F₃N₃O₅S [M+H]⁺: 486.1. found: 486.3, ¹H NMR (400 MHz, MeOD) 8.53 (d, J=11.7 Hz, 2H), 7.92-8.03 (m, 3H), 7.78 (t, J=7.8 Hz, 1H), 4.64 (br s, 1H), 2.96 (br s, 1H), 1.82-1.89 (m, 1H), 1.55 (s, 9H), 0.97 (d, J=6.6 Hz, 3H).

Step 8—Preparation of (R)-7-amino-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3-dihydro-1,5-naphthyridin-4(1H)-one and (S)-7-amino-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3-dihydro-1,5-naphthyridin-4(1H)-one

To a solution of (R or S)-tert-butyl (6-methyl-8-oxo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate (Isomer 1 from Step 7, 10 mg, 0.021 mmol) in DCM (1 mL) was added TFA (2 mL, 26.0 mmol). The reaction mixture was stirred at room temperature for 3 h, then concentrated in vacuo to afford the title compound as colorless oil.

The other enantiomer (Isomer 2 from Step 8) was prepared using a similar procedure as described above from Isomer 2 from Step 7. Both enantiomers have same analysis data: LCMS (ESI) calculated for C₁₆H₁₅F₃N₃O₃S [M+H]⁺: 386.1. found: 386.1.

Step 9. Preparation of (R or S)-1,1,1-trifluoro-2-methylpropan-2-yl (6-methyl-8-oxo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

To a solution of (R or S)-7-amino-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3-dihydro-1,5-naphthyridin-4(1H)-one (Isomer 1 from Step 8, 7 mg, 0.018 mmol) in DMSO (1 mL) was added 3-methyl-1-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-1H-imidazol-3-ium iodide (10 mg, 0.027 mmol). The reaction mixture was stirred at room temperature for 16 h and then purified by prep-HPLC (MeCN/water using TFA buffer) to afford the title compound as a white solid.

LCMS (ESI) calculated for C₂₁H₂₀F₆N₃O₅S [M+H]⁺: 540.1. found: 540.1, ¹H NMR (400 MHz, MeOD) 8.46 (d, J=14.1 Hz, 2H), 7.94 (d, J=16.8 Hz, 3H), 7.76 (t, J=7.8 Hz, 1H), 4.63 (brs, 1H), 2.90 (d, J=10.2 Hz, 1H), 1.85 (brs, 1H), 1.77 (s, 3H), 1.18 (d, J=6.7 Hz, 3H), 0.94 (d, J=6.7 Hz, 3H).

Example 121 Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl ((R and S)-2-((R and S)-5-oxopyrrolidin-2-yl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (Example 121)

Step 1—Preparation of (R and S)-tert-butyl 2-((R and S)-6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-5-oxopyrrolidine-1-carboxylate

A mixture of benzyltriethylammonium chloride (40 mg, 0.176 mmol), K₂CO₃ (122 mg, 0.88 mmol), 2-(benzylamino)-4-nitrophenol (322 mg, 1.32 mmol) and tert-butyl 2-(oxiran-2-yl)-5-oxopyrrolidine-1-carboxylate (200 mg, 0.880 mmol) in DMF (5 mL) was stirred at 100° C. for 16 h. The reaction mixture was diluted with ethyl acetate, washed with brine, dried and concentrated, then purified by prep-TLC (petroleum ether/ethyl acetate=1:1) to afford the title compound as a white solid. LCMS (ESI) calculated for C₂₄H₂₈N₃O₈S [M+H]⁺: 518 found 518.

Step 2—Preparation of (R and S)-5-((R and S)-6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)pyrrolidin-2-one

To a solution of (R and S)-tert-butyl 2-((R and S)-6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-5-oxopyrrolidine-1-carboxylate (400 mg, 0.773 mmol) in DCM (5 mL) was added TFA (441 mg, 3.86 mmol). The reaction mixture was stirred at 30° C. for 6 h, then washed with aq. NaHCO₃ and brine, dried over sodium sulfate, filtered and concentrated to afford the title compounds as yellow oil. LCMS (ESI) calculated for C₁₉H₂₀N₃O₆S [M+H]⁺: 418. found 418, ¹H NMR (400 MHz, CDCl₃) δ 8.19-8.27 (1H, m), 8.08-8.17 (1H, m), 7.82-7.95 (1H, m), 7.67 (2H, brs), 7.32-7.43 (2H, m), 4.20-4.33 (1H, m), 3.67-3.92 (2H, m), 3.44-3.64 (1H, m), 2.46 (3H, s), 2.21-2.43 (4H, m).

Step 3—Preparation of (R and S)-5-((R and S)-6-amino-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)pyrrolidin-2-one

10% Pd/C (122 mg, 0.115 mmol) was added to a solution of (R and S)-5-((R and S)-6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)pyrrolidin-2-one (160 mg, 0.383 mmol) in methanol (10 mL). The reaction mixture was stirred at room temperature for 16 h under a H₂ balloon, then filtered through CELITE and concentrated to afford the titled compound as colorless oil. LCMS (ESI) calculated for C₁₉H₂₂N₃O₄S [M+H]⁺: 388. found 388.

Step 4—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl ((R and S)-2-((R and S)-5-oxopyrrolidin-2-yl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R and S)-5-((R and S)-6-amino-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)pyrrolidin-2-one (9 mg, 0.023 mmol) in DMSO (3 mL) was added 1-iodo-1-methyl-3-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-2,3-dihydro-1H-imidazol-1-ium-2-ide (9 mg, 0.025 mmol) and the resulting mixture was stirred at 20° C. for 1 h. Then water was added and the mixture extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with water and brine, concentrated and the crude product was purified by preparative HPLC (MeCN/water using TFA buffer) to afford the title compound as white solid. LCMS (ESI) calculated for C₂₄H₂₇F₃N₃O₆S [M+H]⁺: 542 found 542. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (1H, br s), 7.60 (2H, d, J=8.2 Hz), 7.30 (2H, d, J=7.8 Hz), 7.19-7.25 (1H, m), 6.78-6.85 (1H, m), 6.47-6.69 (2H, m), 4.05-4.26 (1H, m), 3.77-3.87 (1H, m), 3.63-3.87 (1H, m), 3.31 (2H, d, J=8.2 Hz), 2.43 (3H, s), 2.34-2.41 (3H, m), 1.97-2.11 (1H, m), 1.78 (6H, s).

Biological Assays

The compounds of the invention inhibit RORgammaT activity. Activation of RORgammaT activity can be measured using, e.g., a biochemical TR-FRET assay. In such an assay, interaction of cofactor-derived peptides with human RORgammaT-Ligand Binding Domain (LBD) can be measured. The TR-FRET technique is a sensitive biochemical proximity assay that will give information concerning the interaction of a ligand with the LBD, in the presence of cofactor-derived peptides (Zhou et al., Methods 25:54-61, 2001).

To identify novel antagonists of RORgammaT, an assay was developed which employs the interaction of RORgammaT with its co-activator peptide SRC1_2. This peptide mimics the recruitment of co-activators to RORgammaT through its interaction with the LXXLL (SEQ ID NO:1) (e.g., NR box) motifs (Xie et al., J. Immunol. 175: 3800-09, 2005; Kurebayashi et al., Biochem. Biophys. Res. Commun. 315: 919-27, 2004; Jin et al., Mol. Endocrinology 24:923-29, 2010). The RORγ-Ligand Binding Domain TR-FRET Assay was run according to the following protocol.

HIS-tagged RORγ-LBD protein was recombinantly expressed in Escherichia coli. The RORγ-LBD protein was purified by Ni²⁺-affinity resin. Purified protein was then diluted in assay buffer (50 mM Tris pH 7.0, 50 mM KCl, 1 mM EDTA, 0.1 mM DTT, 100 μg/mL bovine serum albumin, delipidated) to obtain a RORγ-LBD final concentration of 3 nM. Europium tagged anti-HIS antibody was also added to this solution (1.25 nM). Separately, SF9 cells not expressing any recombinant protein were lysed (32,000 cells per μl in 25 mM Tris, 50 mM NaCl) and the previously frozen lysate was added to the diluted RORγ-LBD solution at a ratio of 0.75 μl SF9 lysate per 15 μl of diluted RORγ-LBD.

Compounds to be tested were injected to the 384-well assay plate using Acoustic Droplet Ejection technology by Echo 550 liquid handler (Labcyte, CA).

A stock of biotinylated-LXXLL peptide from coactivator SRC1 (Biotin-SPSSHSSLTERHKILHRLLQEGSP) (SEQ ID NO:2) and APC-conjugated streptavidin (final concentrations 100 nM and 8 nM respectively) were also added to each well.

The final assay mixture was incubated overnight at 4° C., warmed to room temperature and the fluorescence signal was measured on an Envision plate reader: (Excitation filter=340 nm; APC emission=665 nm; Europium emission=615 nm; dichroic mirror=D400/D630; delay time=100 μs, integration time=200 μs). IC₅₀ values for test compounds were calculated from the quotient of the fluorescence signal at 665 nm divided by the fluorescence signal at 615 nm.

The IC₅₀ values for representative compounds of the invention are set forth below.

Ex. No. IC₅₀ (nM) 1 3.011 2A 8.586 2B 8.547 2C 4.571 2D 7.99 2E 237.6 2F 9.743 2G 15.18 2H 11.27 3 325.2 4A 28.44 4B 6.772 5 25.79 6 11.84 7 83.41 8 31.65 9 4.229 10A 41.73 10B 158.9 10C 22.78 10D 10.45 10E 18.36 10F 47.27 10G 29.41 10H 18.97 10i 72.52 10J 10.77 10K 195 11 5.79 12 2.723 13A 7.25 13B 12.72 13C 7.315 13D 11.64 13E 6.611 13F 14.53 13G 56.79 13H 36.86 13i 15.7 13J 5.74 13K 27.75 13L 9.327 13M 5.42 13N 20.02 13o 27.51 13P 15.72 13Q 15.41 13R 24.43 13S 14.6 13T 9.188 13U 8.801 13V 5.297 13W 5.999 13X 10.1 13Y 3.045 13Z 5.817 13AA 5.903 13AB 3.916 13AC 8.073 13AD 5.112 13AE 4.81 13AF 3.928 14 4.129 15A 7.388 15B 9.537 15C 7.751 15D 10.27 15E 5.877 15F 5.184 16 4.16 17A 5.552 17B 11.25 17C 4.808 17D 5.135 17E 7.841 17F 3.861 18 3.276 19A 6.322 19B 13.1 19C 6.113 19D 5.331 19E 5.08 20 10.08 21 692.6 22A 920.1 22B 10.04 23A 4674 23B 27.72 24 11.56 25A 12.33 25B 11.49 25C 623.3 25D 203.1 25E 167.9 25F 9593 25G 51.31 25H 107.6 26 30.68 27 29.17 28A 189.8 28B 20.67 28C 450.5 28D 847.7 28E 189.9 28F 1765 29 3.758 30A 2.241 30B 3.126 30C 2.154 30D 15.83 30E 4.943 31 54.68 32A 16.34 32B 9.557 32C 51.75 32D 19.93 32E 563.2 32F 241.6 32G 81.56 32H 26.59 33 43.31 34A 155.5 34B 60.79 34C 54.12 34D 182.2 34E 58.3 35 17.25 36 10.01 37A 3.889 37B 3.656 37C 7.091 37D 4.805 37E 6.015 37F 11.03 37G 19.84 37H 2.805 37i 4.835 37J 1.961 37K 6.884 37L 7.555 37M 7.898 37N 7.056 37o 5.743 37P 7.645 37Q 10.77 37R 3.79 37S 4.47 37T 19.13 37U 5.462 37V 6.858 37W 9.682 37X 8.031 37Y 10.78 37Z 6.021 37AA 2.526 37AB 45.75 37AC 11.97 37AD 4.711 37AE 4.379 37AF 4.164 37AG 2.557 37AH 2.113 37Ai 13.4 37AJ 5.726 37AK 12.82 37AL 8.413 37AM 6.153 37AN 9.446 37Ao 5.409 37AP 9.273 37AQ 10.16 37AR 17.51 38A 4.691 38B 6.584 38C 6.948 38D 4.871 38E 50.09 38F 42.52 38G 12.5 39 140.4 40 1136 41 36.68 42 19.25 43A 128.5 43B 58.86 43C 41.18 43D 35.53 43E 73.44 43F 50.44 43G 46.62 43H 24.9 43i 26.98 43J 97.22 43K 41.3 43L 91.23 43M 55.32 43N 63.3 43o 110.2 43P 62.94 43Q 36.63 43R 36.23 43S 31.14 43T 60.69 43U 47.48 43V 33.19 43W 534.5 43X 212.8 43Y 72.99 43Z 57.26 43AA 99.03 43AB 85.9 43AC 72.84 43AD 296.8 44 4.073 45A 126.9 45B 12.63 45C 43.79 45D 63.16 45E 25.19 45F 11.25 45G 5.587 45H 14.64 45i 17.1 45J 6.848 45K 6.301 46 12.09 47A 12.26 47B 8.827 47C 5.714 47D 5.982 47E 5.951 47F 27.74 47G 26.58 47H 5.975 48 5.72 49 2.464 50 4.828 51 42.66 52 6.14 53A 4.073 53B 6.26 53C 4.878 53D 5.515 53E 4.379 53F 6.138 53G 7.733 53H 6.766 53i 4.975 53J 6.373 53K 10.55 53L 5.987 53M 15.2 53N 68.44 53o 53.11 53P 3.423 53Q 10.17 54 3.489 55A 3.133 55B 7.848 55C 8.624 55D 136.2 55E 4.09 56 4.919 57A 5.667 57B 3.987 57C 6.441 57D 4.524 57E 4.173 57F 7.503 57G 5.759 57H 10.64 57i 8.268 57J 12.49 57K 10.96 57L 12.5 57M 393.6 57N 30.88 57o 12.83 57P 11.69 57Q 7.383 57R 13.8 57S 14.85 57T 12.7 58 3.564 59 4.77 60 5.973 61 14.9 62 8.874 63A 21.18 63B 9.753 63C 3.037 63D 37.89 63E 2.798 63F 2.782 63G 5.595 63H 8.436 64 16.59 65 4.573 66 6.846 67A 4.899 67B 5.793 67C 23.19 67D 21.57 67E 38.19 72 314.5 73 903.5 74A 194.8 74B 902.5 74C 4955 75 1923 76A 3309 76B 270.2 77 192.2 78A 830 78B 312.6 79A 63.48 79B 130.1 79C 603 79D 189.8 80 330.4 6B 40.02 13AG 5.84 57U 19.43 81A 99.79 81B 28.43 81C 5.137 81D 16.03 81E 9.026 81F 3.325 81G 27.02 82A 231.4 82B 8.849 82C 157.8 82D 7.904 83 4.808 84 7.487 85 13.84 86 64.76 87 232.8 88A 7.651 88B 5.954 89A 22.56 89B 12.94 90A 26.14 90B 6.971 91A 26.14 91B 6.971 91C 6.966 91D 15.85 91E 13.89 91F 18.09 91G 147.7 91H 9.3 91i 24.42 91J 70.36 91K 42.73 92 3.109 93A 5.389 93B 32.15 94A 74.69 94B 4.792 95A 32.31 95B 137.6 95C 78.9 95D 5.727 95E 4.518 95F 524.4 95G 10.12 96 26.17 97A 12.55 97B 29.01 98A 40.06 98B 46.07 98C 1436 98D 29.74 98E 44.81 98F 10.82 98G 38.66 98H 6.325 98i 41.49 98J 28.06 99 8.291 100 10.36 101 11.67 102 11.2 103A 119.7 103B 28.22 104A 11.2 104B 12.65 104C 8.77 104D 11.87 104E 9.238 104F 50.7 104G 119.7 104H 15.24 104i 28.22 105 6.303 106 5.708 107A 6.081 107B 7.533 108 6.621 109A 12.62 109B 39.56 109C 8.263 110 62.3 111A 2724 111B 78.26 112A 72.09 112B 288.9 113 12.35 114A 3.869 114B 4.194 114C 6.863 114D 3.456 115A 2.026 115B 4.961 116A 9.578 116B 8.798 117A 10.47 117B 6.515 117C 7.75 117D 5.748 118 720.5 119 4.49

While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications, and other variations thereof will be apparent to those of ordinary skill in the art in light of the present disclosure. All such alternatives, modifications, and variations are intended to fall within the spirit and scope of the present invention. 

What is claimed is:
 1. A compound of the Formula (I)

or a pharmaceutically acceptable salt thereof, wherein: X¹ is C(R²) or N; X² is O, S, S(O), S(O)₂, CH₂, or C(O); R¹ is H, C₁-C₃ alkyl, or C₁-C₃ alkyl substituted by hydroxy; R² is H, halo, or C₁-C₃ alkyl; R³ is selected from the group consisting of: (a.) H; (b.) C₁-C₆ alkyl; (c.) —(C(R^(a))₂)_(n1)OH; (d.) —(C(R^(a))₂)_(n1)N(R^(b))₂; (e.) —(C(R^(a))₂)_(n1)N(H)C(O)N(R^(b))₂; (f.) —(C(R^(a))₂)_(n1)N(H)C(O)R^(d); (g.) —(C(R^(a))₂)_(n1)N(H)S(O)₂N(R^(b))₂; (h.) —(C(R^(a))₂)_(n1)N(H)S(O)₂R^(d); (i.) —(C(R^(a))₂)_(n2)CO₂R^(c); (j.) —(C(R^(a))₂)_(n2)C(O)N(R^(b))₂; (k.) —(C(R^(a))₂)_(n1)S(O)₂N(R^(b))₂; (l.) —(C(R^(a))₂)_(n2)N(H)C(O)OR^(d); (m.) —(C(R^(a))₂)_(n2)C(O)N(H)S(O)₂R^(d); (n.) —(C(R^(a))₂)_(n1)N(H)S(O)₂OR^(d); (o.) —(C(R^(a))₂)_(n1)S(O)_(n3)R^(d); (p.) —(C(R^(a))₂)_(n2)C(O)N(H)OR^(d); (q.) —(C(R^(a))₂)_(n1)CN; (r.) —C^(H) or —(C(R^(a))₂)_(n1)—C^(H); (s.) —C(R^(a))₂O—C^(C); (t.) —C(O)CF₃; (u.) —OH, with the proviso that R³ is —OH only when X² is CH₂; and (v.) —N(R^(b))₂, with the proviso that R³ is —N(R^(b))₂ only when X² is CH₂; each R^(a) is independently H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, or C₃-C₆ cycloalkyl, or alternatively two R^(a) when bonded to a common carbon atom may together with the common carbon atom form a cyclopropyl ring; each R^(b) is independently: (ii.) H; (ii.) C₁-C₆ alkyl, wherein said C₁-C₆ alkyl is unsubstituted or independently substituted by 1 to 3 fluoro, or hydroxyl; (iii.) —(CH₂)_(n3)CO₂R^(e); or (iv.) —C^(C) or —CH₂—C^(C); or alternatively, two R^(b) together with the N atom to which they are attached form a 5- to 9-membered heterocyclyl, wherein said heterocyclyl is a saturated, partially saturated, or aromatic ring system containing 0, 1, or 2 additional heteroatoms independently selected from the group consisting of N, O, S, and S(O)₂; wherein said heterocyclyl is unsubstituted or substituted by 1 to 4 moieties independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₃ alkoxy, fluoro, hydroxyl, oxo, cyano, amino, C₁-C₃ alkylamino, and C₁-C₃ dialkylamino; R^(c) is (i.) H; (ii.) C₁-C₆ alkyl, wherein said C₁-C₆ alkyl is unsubstituted or independently substituted by 1 to 3 fluoro or hydroxy; or (iii.) —C^(C) or CH₂—C^(C); R^(d) is (i.) C₁-C₆ alkyl, wherein said C₁-C₆ alkyl is unsubstituted or independently substituted by 1 to 3 fluoro or hydroxy; (ii). —C(O)N(R^(f))₂; or (iii.) —C^(C) or CH₂—C^(C); R^(e) is H or C₁-C₃ alkyl; R^(f) is H or C₁-C₃ alkyl; ring C^(H) is (i.) C₃-C₆ cycloalkyl; (ii.) phenyl; or (iii.) a 4- to 9-membered mono- or bicyclic heterocyclyl, wherein said heterocyclyl is a saturated, partially saturated, or aromatic ring system containing 1 to 4 heteroatoms independently selected from the group consisting of N, O, S, and S(O)₂; wherein ring C^(H) is unsubstituted or independently substituted by 1 to 4 C₁-C₆ alkyl, C₁-C₃ alkoxy, halo, hydroxyl, oxo, cyano, amino, C₁-C₃ alkylamino, or C₁-C₃ dialkylamino; ring C^(C) is (i.) C₃-C₆ cycloalkyl; (ii.) phenyl; or (iii.) a heterocyclyl of the formula

 wherein said heterocyclyl is a 5- to 9-membered heterocyclyl, wherein said heterocyclyl is a saturated, partially saturated, or aromatic ring system that contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, S, and S(O)₂; wherein ring C^(C) is unsubstituted or independently substituted by 1 to 4 C₁-C₆ alkyl, C₁-C₃ alkoxy, halo, hydroxyl, oxo, cyano, amino, C₁-C₃ alkylamino, or C₁-C₃ dialkylamino; the subscript n1 is 1, 2, or 3; the subscript n2 is 0, 1, 2, or 3; the subscript n3 is 1 or 2; R⁴ is (a.) C₁-C₈ alkyl, wherein said C₁-C₈ alkyl of R⁴ is unsubstituted or independently substituted by 1 to 6 halo, C₁-C₃ alkoxy, hydroxy, cyano, trimethylsilyl, or methylsulfonyl; (b.) C₂-C₈ alkenyl, wherein said C₂-C₈ alkenyl of R⁴ is unsubstituted or independently substituted by 1 to 6 fluoro or cyano; or (c.) a group of the formula -M-R^(CH); M is (i.) a bond; or (ii.) C₁-C₆ alkylene, wherein said C₁-C₆ alkylene of M is unsubstituted or substituted by 1 to 6 fluoro; R^(CH) is a ring selected from the group consisting of (i.) C₃-C₉ mono- or bicycloalkyl; (ii.) phenyl; and (iii.) a 3- to 6-membered heterocyclyl, wherein said heterocyclyl of R^(CH) is a saturated, partially saturated or aromatic ring system containing 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S; wherein R^(CH) is unsubstituted or independently substituted by 1 to 4 halo, C₁-C₃ alkyl, C₁-C₃ trifluoroalkyl, cyano, C₁-C₄ alkylcarbonylamino, or oxo; Cy is (a.) phenyl; (b.) C₃-C₆ cycloalkyl; (c.) a 5- to 9-membered mono- or bicyclic heterocyclyl, wherein said heterocyclyl of Cy is a saturated, partially saturated, or aromatic ring system containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, S and S(O)₂; or wherein Cy is unsubstituted or independently substituted by 1 to 4 R^(k) moieties selected from the group consisting of: (i.) C₁-C₆ alkyl, wherein said C₁-C₆ alkyl is unsubstituted or independently substituted by 1 to 3 hydroxy or fluoro; (ii.) C₁-C₆ alkoxy, wherein said C₁-C₆ alkoxy is unsubstituted or independently substituted by 1 to 3 fluoro, hydroxy, amino, (C₁-C₃ alkyl)amino, di(C₁-C₃ alkyl)amino, methoxy, or phenyl; (iii.) —N(R^(e1))₂; (iv.) —O(CH₂)_(n4)C(O)N(R^(e1))₂; (v.) —O(CH₂)_(n5)CO₂R^(e1); (vi.) hydroxyl; (vii.) oxo; (viii.) halo; (ix.) C₁-C₃ alkylsulfonyl; (x.) cyano; (xi.) oxetanyl; and (xii.) cyclopropyl; or alternatively, two R^(k) moieties, when substituted on adjacent ring atoms of Cy, form a second ring, wherein said second ring is a 5- to 7-membered saturated, partially saturated, or aromatic ring system that contains 0, 1, or 2 heteroatoms independently selected from the group consisting of N, O, and S; wherein said second ring is unsubstituted or substituted by 1 to 3 R^(k) moieties independently selected from (i)-(xi); each R^(e1) is independently H or C₁-C₃ alkyl; the subscript n4 is 1, 2, or 3; and the subscript n5 is 1, 2, or
 3. 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein (a.) X¹ is C(R²) and X² is O; (b.) X¹ is N and X² is O; or (c.) X¹ is N and X² is CH₂.
 3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R⁴ is a group of the formula


4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R¹ is H or methyl.
 5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Cy is a group of the formula

wherein the subscript s is 0, 1, 2, or
 3. 6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R³ is a group of the formula —(C(R^(a))₂)_(n1)N(H)S(O)₂N(R^(b))₂.
 7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein the subscript n1 is
 1. 8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein each R^(b) is independently: (i.) H; (ii.) C₁-C₄ alkyl, wherein said C₁-C₄ alkyl is unsubstituted or substituted by 1 to 3 fluoro; (iii.) —C^(C); alternatively, two R^(b) together with the N atom to which they are attached form a 5- to 6-membered heterocyclyl, wherein said heterocyclyl is selected from the group consisting of pyrrolidinyl, piperidinyl, and morpholinyl; wherein said heterocyclyl is unsubstituted or substituted by 1 to 2 moieties independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₃ alkoxy, fluoro, hydroxyl, oxo, cyano, amino, C₁-C₃ alkylamino, and C₁-C₃ dialkylamino; and ring C^(C) is C₃-C₆ cycloalkyl; wherein ring C^(C) is unsubstituted or independently substituted by 1 to 2 C₁-C₆ alkyl, C₁-C₃ alkoxy, halo, hydroxyl, oxo, cyano, amino, C₁-C₃ alkylamino, or C₁-C₃ dialkylamino.
 9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X¹ and X² are as follows: (a.) X¹ is C(R²) and X² is O; (b.) X¹ is N and X² is O; or (c.) X¹ is N and X² is CH₂; R¹ is H or methyl; R² is H; R³ is —(C(R^(a))₂)_(n1)N(H)S(O)₂N(R^(b))₂; R⁴ is a group of the formula

 and Cy is a group of the formula

 wherein the subscript s is 0, 1, 2, or
 3. 10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein X¹ is C(R²) and X² is O.
 11. The compound of claim 9 or 10 or a pharmaceutically acceptable salt thereof, wherein each R^(b) is independently: (i.) H; (ii.) C₁-C₄ alkyl, wherein said C₁-C₄ alkyl is unsubstituted or substituted by 1 to 3 fluoro; (iii.) —C^(C); alternatively, two R^(b) together with the N atom to which they are attached form a 5- to 6-membered heterocyclyl, wherein said heterocyclyl is selected from the group consisting of pyrrolidinyl, piperidinyl, and morpholinyl; wherein said heterocyclyl is unsubstituted or substituted by 1 to 2 moieties independently selected from the group consisting of C₁-C₆ alkyl, C₁-C₃ alkoxy, fluoro, hydroxyl, oxo, cyano, amino, C₁-C₃ alkylamino, and C₁-C₃ dialkylamino; and ring C^(C) is C₃-C₆ cycloalkyl; wherein ring C^(C) is unsubstituted or independently substituted by 1 to 2 C₁-C₆ alkyl, C₁-C₃ alkoxy, halo, hydroxyl, oxo, cyano, amino, C₁-C₃ alkylamino, or C₁-C₃ dialkylamino.
 12. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1-11 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
 13. The pharmaceutical composition of claim 12, further comprising an additional therapeutic agent.
 14. A method of treating a disease or condition mediated by RORgammaT comprising administering a therapeutically effective amount of the compound of any one of claims 1-11 or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.
 15. The method of claim 14, further comprising administering an additional therapeutic agent to the patient.
 16. Use of the compound of any one of claims 1-11 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease or condition mediated by RORgammaT. 